Accelerated Atherosclerosis in Metabolic Syndrome & Type II Diabetes

[Guest guest]

Intimal redox stress:

 

Accelerated atherosclerosis in metabolic syndrome and type 2 diabetes mellitus.

Atheroscleropathy

Melvin R Hayden1 and Suresh C Tyagi2

 

1Adjunct Assistant Professor Department of Family and Community Medicine

University of Missouri Columbia, Missouri, USA

2Assistant Professor Department of Physiology and Biophysics University of

Mississippi Medical Center Jackson, Mississippi 39216-4505, USA

 

Cardiovascular Diabetology 2002, 1:3

 

The electronic version of this article is the complete one and can be found

online at: http://www.cardiab.com/content/1/1/3

 

Received 18 August 2002

Accepted 27 September 2002

Published 27 September 2002

 

© 2002 Hayden and Tyagi; licensee BioMed Central Ltd. This is an Open Access

article: verbatim copying and redistribution of this article are permitted in

all media for any purpose, provided this notice is preserved along with the

article's original URL.

--

Keywords: Atherosclerosis, Atheroscleropathy, Oxidative stress, ROS (reactive

oxygen species), RNS (reactive nitrogen species), Reductive stress

 

Abstract

 

 

 

Metabolic syndrome, insulin resistance, prediabetes, and overt type 2 diabetes

mellitus are associated with an accelerated atherosclerosis (atheroscleropathy).

This quartet is also associated with multiple metabolic toxicities resulting in

the production of reactive oxygen species. The redox stress associated with

these reactive oxygen species contribute to the development, progression, and

the final fate of the arterial vessel wall in prediabetic and diabetic

atheroscleropathy. The prevention of morbidity and mortality of these

intersecting metabolic diseases can be approached through comprehensive global

risk reduction.

 

 

 

Metabolic syndrome (MS), insulin resistance (IR), prediabetes (PD), and overt

type 2 diabetes mellitus (T2DM) amplifies and accelerates the risk of

atherosclerosis with its associated effect on morbidity and mortality.

 

The multiple toxicities of this quartet: MS, IR, PD which includes impaired

glucose tolerance (IGT) and impaired fasting glucose (IFG), and overt T2DM

result in accelerated atherosclerosis (macrovascular disease) or

atheroscleropathy in addition to microvascular disease. It is appropriate to set

forth definitions for this discussion.

 

Definition

 

Working definition of atherosclerosis:

 

Atherosclerosis is a systemic dysfunctional endothelial, focal occurring,

chronic inflammatory, fibroprolifertive, angiogenic, prothrombotic,

multifactorial disease of the arterial intima caused by the retention of

modified low density lipoproteins, hemodynamic, and redox stress [1-4] (figure

1) (figure 2).

 

Working definition of atheroscleropathy:

 

Atheroscleropathy: The term used to describe the unique accelerated

atherosclerosis observed in and associated with MS, IR, PD, and overt T2DM.

 

Henceforth, in this review the term atheroscleropathy shall be used to describe

accelerated atherosclerosis associated with MS, IR, PD, and overt T2DM.

 

Three quarters of a century ago, a quote from Elliott P Joslin's presentation to

the American College of Physicians in 1927 seems appropriate.

 

 

 

" I believe the chief cause of premature development of arteriosclerosis in

diabetes, save for advancing age, is due to an excess of fat,

an excess of fat in the body,

obesity, an excess of fat in the diet,

and an excess of fat in the blood.

 

With an excess of fat diabetes begins and from an excess of fat diabetics die,

formerly of coma, recently of arteriosclerosis. " [5] Refer to A-FLIGHT toxicities

sections (F), (L), (T).

 

This master clinician of diabetes was one of the first physicians to make the

association regarding the double jeopardy of type 2 diabetes mellitus and

atheroscleropathy with its associated morbidity and mortality in cardiovascular

disease.

 

Recognition of the prophetic view of Joslin has now been fulfilled in the 2001

National Cholesterol Education Program Adult Treatment Panel III guidelines.

Diabetes (both T1DM and T2DM) is now considered a coronary risk equivalent and

the metabolic syndrome is included in the multiple risks factors for the

development of atheroscleropathy. [6]

 

For today's atherosclerologists the history of atherosclerosis is rich and the

theories are legion. Even today, knowledge in this field of study is expanding

exponentially. In this review, we will try to remain focused on intimal redox

stress and how this interacts with the manifold toxicities of IR, MS, PD, and

T2DM to result in a unique accelerated atherosclerosis which shall be called

atheroscleropathy.

 

Redox homeostasis, redox stress, and oxidative stress

 

Cellular respiration (the transference of electrons between oxygen species)

allows each of us to survive on this planet not only at the cellular level but

also as an organism. Homeostasis is a key element to all healthy physiologic

functions throughout the body and when there is loss of homeostasis, there is

usually disease.

 

Redox homeostasis describes the normal physiologic process of reduction and

oxidation in order to re-pair unstable, damaging, reduced, reactive oxygen

species (ROS) which will include the following oxygen free radicals (O2' –

superoxide,

H2O2 – hydrogen peroxide,

-OH' hydroxyl radical, and singlet oxygen)

and organic analogues which include reactive nitrogen species (RNS) primarily

peroxynitrite ONOO'.

 

This homeostatic balance between ROS and antioxidant capacity is in contrast to

redox stress (redox imbalance) which implies a loss of this unique homeostasis

resulting in an excess production of ROS (tables 1 and 2) either through the

process of reduction or oxidation.

 

Oxidative Stress implies a loss of redox homeostasis (imbalance) with an excess

of ROS by the singular process of oxidation. Both redox and oxidative stress may

be associated with an impairment of antioxidant defensive capacity as well as an

overproduction of ROS.

 

It has been known for some time that ROS are detrimental and toxic to cells and

tissues as a result of injury to lipids, nucleic acids, and proteins: (A). Lipid

peroxidation of membranes (loss of membrane function and increased permeability)

and generation of lipid autoperoxidation reactions. (B). DNA damage leading to

mutation and death. ©. Cross linking or vulcanization of sulfhydryl rich

proteins (leading to stiff aged proteins specifically collagen of the

extracellular matrix). [7]

 

The evolutionary process of redox homeostasis allows humans to survive in an

atmosphere of high oxygen content. In addition our bodies have become " hard

wired " to utilize the mechanism of redox stress injury to fend off invading

infectious organisms and survive our environment.

 

Paradoxically, (when there is loss of homeostasis resulting in redox or

oxidative stress) this protective mechanism turns on our own cells; tissues and

causes damage, especially the intima in the atheroscleropathy associated with

MS, IR, PD, and overt T2DM. This constellation of MS, IR, PD, and T2DM is

associated with an elevated tension of redox stress within the intima (also the

islet in MS, IR, PD, and T2DM) due to multiple toxicities. (table 3) Each of

these A-FLIGHT toxicities result in the formation of damaging ROS. [8,9]

 

Not only are ROS involved in the development of type 1 diabetes mellitus (T1DM)

and T2DM but also play an important role in the long-term development of the

associated complications:

 

The multiple diabetic-opathies (A – DINNER: atheroscleropathy, angiogenesis

(accelerated) and arteriogenesis (impaired), diabetic cardiomyopathy and

dermopathy, intimopathy, nephropathy, neuropathy, enteropathy, retinopathy

(table 4). This review will focus primarily on the association of redox stress

in the intima and how it interacts with MS, IR, PD, and T2DM.

 

Metabolic syndrome and insulin resistance

 

IR describes the condition whereby there is a resistance to insulin mediated

glucose uptake by cells and is central to the clustering of multiple metabolic

abnormalities and clinical syndromes (figure 3). The clustering phenomenon was

first described by Kylin in 1923 when he described the clustering of three

clinical syndromes: hypertension, hyperglycemia, and hyperuricemia. [10]

 

In 1936 Himsworth [11] noted that a large number of diabetic patients were

insulin insensitive and suggested that diabetics be divided into groups that

were insulin sensitive and insulin insensitive.

 

Yalow and colleagues in 1965 [12] were first to discover an insulin assay and

reported that IR was a condition in which insulin does not produce the same

glucose lowering effects seen in insulin-sensitive individuals.

 

These concepts were rejuvenated and immortalized by Reaven in 1988 given as the

Banting lecture.[13] The clustering phenomenon has gone by many names since Dr.

Reaven first described the metabolic and clinical associations of the many names

of Syndrome X. (table 5)

 

By 1999, the World Health Organization had chosen a unifying definition for this

syndrome of many names and elected to use the term metabolic syndrome rather

than the insulin resistance syndrome because they felt it was not well

established that insulin resistance was the cause of all components of the

syndrome.[14]

 

Additionally, there are at least a dozen factors that link clinical suspicions

to the metabolic syndrome. (table 6) Factors and findings in this syndrome occur

together all to frequently to be considered a coincidence and there are common

underlying factors that may explain this coexistence. Namely, the well

documented hyperinsulinemia story and the more recent hyperamylinemia and amylin

derived islet amyloid story. [8,9]

 

MS affects approximately 47 million or greater Americans. [15] Of these 47

million, only 20% will develop T2DM and the remaining 80% will be able to

compensate (at least for a period of time) through the process of beta cell

expansion, hypertrophy, and hyperplasia (utilizing the replicative pool of

periductal cells). [16,17]

 

The resulting hyperinsulinemia, hyperamylinemia (37.6 million = 80% of 47

million) does not come without a price to pay as this compensatory mechanism

places these patients at risk for hypertension, atheroscleropathy, and

subsequent coronary artery disease. [18,19] (figure 3) See section (A). Ang II,

(A). Amylin toxicity, and (I). Insulin toxicity.

 

The manifold – A-FLIGHT toxicities

 

(A). Angiotensin II toxicity

 

Angiotensin II (Ang II) is associated with hypertension, MS, IR, PD, and T2DM

both systemically and at the local tissue level. Currently, there is evidence

that a local tissue renin angiotensin aldosterone system (RAAS) is operative

within the intima and islet as angiotensin type one (AT-1) receptors have been

identified as being present on smooth muscle cells, endothelial cells, and the

beta cells within the intima and islet [20,21]

 

Insulin is known to upregulate the AT-1 receptor [22] and there exists cross

talk between the insulin and the Ang II signaling systems [23] In 1995, Copper

et al. were able to demonstrate that amylin activates the RAAS with elevations

in renin and aldosterone in humans [24] and, in 2001, Ikeda et al. were able to

demonstrate that insulin, proinsulin and amylin infusions resulted in

significant increases in renin release and that proinsulin and amylin enhanced

this insulin-stimulated renin release in the perfused rat kidney [25].

 

Taken together, these data support the strong influence of a local RAAS

mechanism operating within the intima and islet for the local production of

excess Ang II. The islet is quite vascular with an abundant supply of intra

islet capillaries and endothelial cells and the intima is lined by a continuous

monocellular layer of endothelial cells (additionally, the arterial vessel wall

becomes highly vascular through the process of plaque angiogenesis as the

vulnerable plaque evolves during the process of atheroscleropathy).

 

This allows the vascular NAD(P)H oxidase enzyme to come into play. Ang II is one

of the most potent endogenous stimuli for the generation of superoxide O2- via

the activation of vascular NAD(P)H oxidase. [26,27]

 

The interruption of this mechanism by the angiotensin converting enzyme

inhibitor (ACEi) ramipril in the Heart Outcomes Prevention Evaluation (HOPE)

study may help to explain the 32% risk reduction for developing T2DM as well as

the dramatic reduction in cardiovascular events. [28]

 

A special reference to Griendling and Harrison seems appropriate: " Out, damned

DOT! Out I say " (where the damned DOT represents the unpaired dots on Lewis

diagrams). [29] One of the best ways to prevent these dots from forming is to

prevent excess substrates (table 3) which cause the multiple toxicities and the

multiplicative effect of the A-FLIGHT toxicities associated with MS, IR, PD, and

T2DM.

 

In MS, IR, PD, and T2DM the intima and islet milieu will be laden with the

necessary substrates (hyperinsulinemia, hyperproinsulinemia and hyperamylinemia)

to activate the damaging cascading mechanism of Ang II, NAD(P)H oxidase,

superoxide (O2-) and peroxynitrite (ONOO-) production while consuming the

natural endogenously produced antioxidant nitric oxide (NO) within the

vulnerable intima and islet.

 

(A). Advanced glycosylation endproducts: AGE

 

Advanced glycosylation endproducts (AGEs) are formed as a result of the

non-enzymatic damaging protein glycation due to an excess of glucose

(hyperglycemia) present in both T1DM, PD, and T2DM. AGEs are initially formed

through the process of a glucose nucleophilic addition reaction with proteins

forming a Schiff base followed by the formation of an Amadori compound which

undergoes further reactions, rearrangements, dehydrations and cleavage resulting

in brown insoluble, cross linked complexes called AGEs. This process is thought

to liberate H2O2 through two pathways: the first is the 1,2-enolization pathway

which leads to 3-deoxyglucosone forming H2O2 and glucosone; the second pathway

is the 2,3-enolization pathway leading to 1-deoxyglucosone and putative

1,4-deoxyglucosone. Under oxidative conditions, the 2,3-enediol is thought to

generate H2O2 and carboxymethyllysine. 3-deoxyglucosones are known to be both

highly reactive intermediates in non-enzymatic glycosylation and also potent

cross-linkers which are responsible for the polymerization of proteins to AGEs.

These highly cross-linked proteins, especially collagen, cause a stiffening

within the vessel which results in decreased compliance of the arterial vessel

wall and may well play an important role in the development of diabetic

diastolic dysfunction, diabetic cardiomyopathy, and the diastolic dysfunction of

the arterial vessel wall. Furthermore, there are advanced fructosylation

endproducts (AFEs), which actually have a greater affinity binding to proteins

than glucose and follow a similar pattern in the production of the ROS. [30-33]

An excellent in depth review of AGE can be found in an article by Aronson and

Rayfield where they discuss how hyperglycemia promotes atherosclerosis [34].

 

The multiligand immunoglobulin superfamily cell surface receptor: the receptor

for advanced glycation endproducts (RAGE) is up-regulated by the presence of AGE

and results in the signal transduction of nuclear factor kappa B (NFkappa B)

which then results in a chronically active inflammatory state and links this

section to section (I). Inflammation Toxicity and atheroscleropathy. [35,36]

 

(A). Antioxidant enzymes

 

Antioxidant reserve compromised

 

In addition to the excess generation of the ROS seen in diabetes, there exists

an impaired generation of endogenous antioxidants. Superoxide dismutase (SOD),

[37] glutathione reduced (GSH), [38] and ascorbic acid (Vitamin C) [39] are all

decreased and associated with atheroscleropathy in diabetes. Moreover, there is

evidence of the diminished capacity of other antioxidants such as uric acid and

vitamin E with a reduced activity of catalase and glutathione peroxidase (GPx).

(Table 6) [40] The exact mechanisms of impairment are still not completely

understood but two explanations exist.

 

Protein glycation may be a mechanism that damages the protein within the primary

antioxidant enzymes, and the antioxidant enzymes which are co-dependent on one

another, may be dysfunctional if one or the other is being consumed by an

overactive demand such as compromised GSH function due to the depletion of NADH

in the polyol pathway.

 

It seems quite logical that both mechanisms may be in play at one time or

another in the diminished antioxidant defense mechanisms. Another example is

glutathione disulfide (GSSG) which is reduced to GSH at the expense of NAD(P)H.

[41]

 

Absence of network antioxidant enzymes

 

eNOS

 

The absence of network antioxidant enzymes could play an additional role. A good

example of this condition would be the endothelial nitric oxide synthase (eNOS)

-/- knockout mouse model by Duplain and Scherrer.

 

They were able to demonstrate that insulin resistance, hyperlipidemia, and

hypertension were present in mice lacking the specific isoform eNOS. This

implicates eNOS not only in the endothelial cell (important in the regulation of

arterial pressure) but also in the loss of its expression in skeletal muscle

which impairs insulin stimulated glucose uptake, and that its loss (both at the

endothelial and skeletal muscle sites) impairs lipid homeostasis and creates

insulin resistance. [42]

 

This represents the loss of the naturally occurring free oxygen radical

scavenging antioxidant effect of endothelial nitric oxide (eNO) (Table 7). Does

this apply to humans?

 

There is evidence of a gene polymorphism in humans and recently Miyamoto et

al.[43] were able to demonstrate that a gene polymorphism, Glu298Asp in exon 7

of the eNOS gene, was associated with coronary spastic angina and myocardial

infarction and found further evidence for this gene polymorphism in the

statically significant association with the development of essential

hypertension in two separate Japanese populations. There could be other gene

polymorphisms in other populations as well as in other antioxidant genes that

relate to insulin resistance, metabolic syndrome, and hypertension. As the human

genome evolves, we are certain to find other alterations in various populations

throughout the world.

 

Asymmetrical dimethylarginine (ADMA) has recently been shown to be associated

with endothelial dysfunction and increased risk of cardiovascular disease.

Stuhlinger, Reaven, Tsao, and colleagues were able to demonstrate a positive

correlation with impaired insulin-mediated glucose disposal and elevated levels

of ADMA. Plasma ADMA concentrations increased in insulin-resistant subjects

independent of hypertension. Increases in plasma ADMA concentrations may

contribute to the endothelial dysfunction observed in insulin-resistant

patients.

 

Elevated levels of ADMA have been observed in IR, hypertension, hyperlipidemia,

hyperglycemia, hyperhomocysteinemia, and renal failure. ADMA is formed by

protein arginine N-methyltransferases and LDL-C both native and oxidized up

regulates PRMT's increasing ADMA. [44,45]

 

Under physiologic homeostatic conditions, eNOS is the endothelial constitutive

(rate limiting) enzyme responsible for the conversion of L-arginine to NO and

L-citrulline. It requires a cofactor tetrahydrobiopterin (BH4). There is a

paradoxical uncoupling of the eNOS enzyme that allows this above reaction to be

capable of producing superoxide (O2') if there is insufficient BH4, L-arginine,

or if there is direct interference with and/or defect in the eNOS enzyme.

Uncoupling of eNOS enzyme results in the production of damaging O2' adding to

the oxidative stress within the arterial vessel wall.

 

Causative factors for eNOS uncoupling are as follows: Increased O2' and ONOO',

elevations in glucose and both native LDL-C and oxidatively modified, mmLDL-C,

hyperhomocysteinemia see section (H), decreased or impaired Cofactor BH4,

decreased L-arginine, increased ADMA, and C reactive protein. In time there will

in all probability be other causative factors that disable the eNOS enzyme

resulting in increased oxidative stress. Additionally, diabetic endothelium has

been shown to be a net producer of superoxide O2' instead of nitric oxide NO

resulting in a decreased ratio of NO / ROS [46-51] (figure 4)

 

The ROS stemming from the A-FLIGHT toxicities additionally play a role in the

competitive inhibition of eNOS. Redox stress results in the production of

nitroarginine as well as nitrotyrosine. Nitroarginine then competes with

L-arginine as a substrate for eNOS to generate NO. Stepp and colleagues were

able to demonstrate a 4 fold increase in O2' and an 8 fold increase in O2' when

endothelial cells were exposed to native LDL-C and mmLDL-C respectively. This

uncoupling of eNOS plays an important role in endothelial cell dysfunction and

increased oxidative stress. [47] Hyperglycemia and peroxynitrite (ONOO') also

induce eNOS uncoupling with increases in O2' production. [48] Just published,

Verma S and colleagues reported that CRP caused a marked down regulation of eNOS

mRNA and protein expression with subsequent lower eNO production. The authors

point out that CRP may not just be a marker of atherosclerosis and increased

risk of acute coronary events, but may also be a mediator of this

disease process. Strategies designed to lower CRP may reduce cardiovascular

risk by directly improving bioavailability of NO and endothelial function. [49]

See section (I). Inflammation.

 

There are undoubtedly many more scenarios in which eNOS can be impaired with

resulting decreased NO but at this point in time it is certainly interesting to

see a tight connection of impaired eNOS and the MS, IR, PD, and T2DM.

Additionally, the synergistic importance regarding elevations of both glucose

and native LDL-C or mmLDL which result in elevations of the detrimental

superoxide (O2') can uncouple the eNOS enzyme leading to even further increases

in O2'. The importance of treating LDL-C, HbA1c, and hypertension to goal are

therefore paramount in reducing the oxidative damage and endothelial cell

dysfunction. (table 9) (figure 6) These examples only strengthen the statement

that ROS beget ROS.

 

The synergism and the vicious cycle of redox and oxidative stress to the

arterial vessel wall from ROS produced by vascular cells, especially the

endothelium, as a result of the A-FLIGHT toxicities necessitates an aggressive

global approach. Wong T.Y. and colleagues for the Atherosclerosis Risk In

Communities (ARIC) Investigators were able to show that retinal arteriolar

narrowing was independently associated with the risk of developing future

diabetes. This supports a microvascular role in the development of clinical

diabetes and provides clinical evidence to support a hypothesis that eNOS and

endothelial dysfunction may be implicated in the pathogenesis of diabetes. This

new clinical information, of arteriolar narrowing preceding the clinical onset

of diabetes and implicating endothelial cell dysfunction (including an eNOS

defect) could play a major important role in the development of this polygenic –

multifactorial disease of MS, IR, PD, overt T2DM and atheroscleropathy. [52]

 

This leads to an interesting Hypothesis:

 

Could it be that T2DM is really a cardiovascular disease (evolving around a

primary eNOS enzyme dysfunction or defect with an effect on MS and IR) with a

late manifestation of glucose elevation i.e. PD and overt T2DM? This would

certainly tie the natural history of T2DM and atheroscleropathy together [53].

 

Other antioxidant enzymes

 

If any one of the antioxidant enzymes (table 7) is missing or impaired or any

combination of them are impaired, then we would expect to see a similar event as

in the knockout mouse model. It would not have to be a complete knockout of the

enzyme, as discussed above, as various gene polymorphisms could exist which

could result in a decreased antioxidant reserve.

 

(A). Ageing

 

Ageing has been shown to be associated with an increased risk of developing T2DM

and atheroscleropathy. Ageing allows the multiplicative effects of the A-FLIGHT

toxicities to become manifest. Advanced ageing leads to impaired endothelial

nitric oxide synthesis and also enhanced endothelial apoptosis.

 

In addition, aged cells have a significantly enhanced concentration (more than 3

fold) of oxidized low density lipoprotein, TNFalpha and caspase-3 activity as

compared to young cells. The decrease in eNO associated with aged cells creates

a deficiency of the naturally occurring antioxidant eNO. [54]

 

Similarly, excess redox stress is felt to contribute to ageing. Information on

the relationship of redox stress and ageing and inflammation (see section " (I).

Inflammation Toxicity " ) is rapidly increasing and gaining wider recognition.

[55,56]

 

(A). Amylin toxicity

 

Amylin, also termed islet amyloid polypeptide (IAPP) is a 37 amino acid

polypeptide co-synthesized, co-packaged, and co-secreted by the islet beta cell

with insulin. It may be considered insulin's a fraternal twin.

 

Amylin parallels insulin synthesis, secretion, and excretion so that whenever

you have hyperinsulinemia you have hyperamylinemia and, in the same way, when

insulin levels decline amylin levels decline.

 

Amylin stimulates lipolysis in vivo and may be a possible mediator of induced

insulin resistance. Ye et al., were able to demonstrate that amylin infusion (5

nmol/h for 4 h) conscious rats that fasted for 5–7 hours resulted in an

elevation of insulin, lactate and glucose (P < 0.05 vs. control).

 

Despite the rise in insulin, plasma non-esterified fatty acid and glycerol were

also elevated (P < 0.001). Although the plasma triglyceride content was

unaltered, the triglyceride content in the liver was increased by 28% (P <

0.001) with a similar tendency in muscle (18%, P = 0.1). These effects were

blocked by the rat amylin antagonist amylin-(8–37) and also by the

anti-lipolytic agent acipimox. The authors concluded that amylin could exert a

lipolytic-like action in vivo. [57]

 

This elevation in amylin would correspond to the insulin resistant state with

associated elevation in amylin in humans. These data indicate that amylin may

play a role by elevating free fatty acids which would aggravate or induce the

underlying insulin resistance and provide a mechanism for increasing the free

fatty acid substrate for increased redox stress, cytotoxicity and intimal

remodeling associated with atheroscleropathy.

 

There are amylin binding sites within the renal cortex and amylin activates the

RAAS with elevations in renin and aldosterone [24]

 

These findings suggest that glucotoxicity resulting in AGE formation both

promotes and accelerates redox stress. [58]

 

Janson et al. have found that intermediate sized toxic amyloid particles

(ISTAPs) have been found to be cytotoxic to beta cells inducing apoptosis by

membrane disruption. [59]

 

(A). Angiogenesis (accelerated): Arteriogenesis (impaired): Vascularization

Paradox In T2DM

 

The process of Angiogenesis starts with capillaries and ends with more

capillaries

 

As the atheroma matures there is an associated intense plaque angiogenesis

arising primarily from the adventitial vasa vasorum (atherosclerotic

intimopathy). These vessels invade the arterial vessel wall in a malignant like

fashion.

 

This plaque vascularization (angiogenesis) corresponds to the presence of the

inflammatory infiltrate at the shoulder of these lesions, the development of the

large lipid core, the thin fibrous cap, and the decrease in SMCs within the

fibrous cap, to form, what we now term the vulnerable plaque. [1-4]

 

Extensions of the vasa vasorum (the vessels within a vessel) act as a custom

delivery system within the vessel walls' vulnerable shoulder region supplying:

1. substrates of the RAAS; 2. substrates of native LDL-C; 3. the second wave of

inflammatory cells; 4. inflammatory mediators (various cytokines and growth

factors); and 5. provide an additional conduit and source of redox stress at the

endothelial cell – extracellular matrix interface within these vulnerable

plaques.

 

This process is accelerated in the MS, IR, PD, and T2DM as well as the T1DM

patient. Vasa vasorum derived fragile capillary-like vessels are prone to

rupture and create intra plaque hemorrhages (IPH) which destabilize the plaque

and promote the possibility of being prone to rupture with ensuing

cardiovascular events. The pseudohypoxia (increased ratio of NADH/NAD+ discussed

by Williamson and Kilo see section (G) glucotoxicity.) in the polyol-sorbitol

pathway as well as the true hypoxia induced by the increasing intima media

thickness may act to induce the nuclear hypoxia inducible factor (hif-1) within

the smooth muscle and endothelial cells which result in the increased expression

of vascular endothelial growth factor VEGF which is so central and vital to the

angiogenic process. This diabetic atherosclerotic intimopathy (plaque

angiogenesis) would be akin to the diabetic retinopathy. [3,60-62]

 

The process of arteriogenesis starts with small arterioles and ends with larger

arterioles

 

In contrast the vascularization process of arteriogenesis is impaired. Even

though patients with diabetes (both T1DM and T2DM) have a much higher number of

atherosclerotic diseased arteries, mean coronary collateral vessels (CCV) are

significantly decreased. [63]

 

Elevations in plasminogen activator inhibitor-1 (PAI-1) are present in the MS,

IR, PD, and T2DM patient. Remodeling collateralization (arteriogenesis) is

stimulated by the tissue and urokinase plasminogen activators (tPA and uPA).

PAI-1 elevations decrease the conversion of plasminogen to plasmin because it

inhibits tPA and uPA. As plasmin is impaired there is a reduction of the

conversion of inactive or pro-MMP-1 to active MMP-1 with inhibition of ECM

turnover with resultant impaired CCV formation. This paradox in diabetes

vascularization contributes greatly to the known poor outcomes associated with

cardiovascular events in the diabetic. [3]

 

(A). Atherosclerosis and atheroscleropathy

 

Once atherosclerosis and atheroscleropathy has been initiated and sustained,

this process is self – perpetuating (self sustaining) and the vicious cycle of

ROS begetting ROS comes into play with all of its inherent complications. It's

as if the multiple A-FLIGHT toxicities polymerize with redox stress and its

associated ROS acting as an accelerant. The associated ischemic cardiomyopathy

and the distinct diabetic cardiomyopathy are not within the scope of this

review.

 

(F). Free fatty acids

 

Free fatty acid (FFA) elevation is known to be associated with IR, MS, PD, and

T2DM. The metabolically active form of FFAs are cytosolic long-chain acyl-CoA

esters (LCACoA) and are responsible for cytosolic neutral triglyceride

deposition in adipose and non-adipose tissues.

 

In 2001, McGarry gave an excellent presentation at the American Diabetes

Association meeting (ADA 2001 Banting Lecture), discussing in detail how toxic

FFA and LCACoA may be important in the development of insulin resistance,

progressive beta cell dysfunction and death associated with T2DM. [64]

 

Central obesity is associated with increased cytosolic neutral fat triglyceride

stores in adipose and non-adipose tissues such as muscle (skeletal and cardiac),

the liver, pancreatic beta cells and, possibly, endothelial cells. [64,65]

 

Intra-myocellular lipid was found to be more highly correlated with insulin

resistance than any other commonly measured indices such as body mass index,

waist-to-hip ratio or total body fat. Low insulin sensitivity was accompanied by

a marked increase in intra-myocellular lipid. Bakker et al.[65] proposed that

the chronic low-grade production of ROS produced by respiring mitochondria is

enhanced by excessive cytosolic triglyceride stores and LCACoA esters in

non-adipose tissue.

 

They proposed that LCACoA esters exert an inhibitory effect on the adenosine

nucleotide translocator with a resultant decrease in the ADP available. This

decrease in ADP slows the flow of electrons along the electron transfer chain

and increases the possibility of having single unpaired electrons to create the

superoxide anion (O2-) increasing oxidative mitochondrial stress, thus resulting

in a dysfunctional cell. Moreover, they suggest that these phenomena not only

accelerate the atherosclerotic process but also induce endothelial dysfunction

and microalbuminuria prior to the development of T2DM and possibly beta cell

dysfunction and failure. [65]

 

It is difficult to completely separate FFA toxicity from the sections which

follow on lipoprotein toxicity and triglyceride toxicity as there is a dynamic

relationship between these three in the A-FLIGHT toxicities. In fact, FFAs are

transported by the protein fraction, albumin, and lipases are constantly

removing the long chain fatty acids from the glycerol backbone of triglycerides

at the interface of the capillary endothelial cells creating free fatty acids

which can freely move into cells throughout the body. Intracellularly, the FFAs

are then added to the glycerol backbone in order to form cytosolic triglycerides

stored as neutral fat, or are oxidized for fuel and energy generating ATP. If

mitochondrial beta oxidation is over utilized or dysfunctional, the excess may

then undergo the toxic non-beta non-mitochondrial pathway generating toxic FFAs

or ceramide (see section " (L). Lipotoxicity – Specific " ).

 

L). Lipotoxicity – generalized

 

Lipotoxicity promotes oxidative stress and is associated with MS, IR, PD, and

T2DM. There is an associated defect of lipoprotein metabolism frequently

referred to as the " lipid triad " . Elevated VLDL or triglycerides, atherogenic

small dense LDL, and decreased HDL comprise this triad which is associated with

atheroscleropathy and coronary heart disease as well as increased redox stress.

[66-68]

 

The increased VLDL, triglycerides, atherogenic small dense LDL cholesterol and

the diminished amount of the anti-atherogenic, antioxidant anti-inflammatory

high density lipoprotein cholesterol would reduce the natural antioxidant

reserve. This combination supports an increase in redox stress in addition to

the previously discussed FFA toxicity. This also tends to support the oxidation,

glycation and glycoxidation of existing lipoproteins (modification) which

results in increased ROS and redox stress.

 

Lipoproteins have the function of transporting lipids throughout the body. Low

density lipoproteins are responsible primarily for the transport of cholesterol

with the protein moiety involved: apolipoprotein (Apo) B 100. Very low density

lipoproteins are responsible for the transport of triglycerides with the protein

moiety involved: Apo E. High density lipoproteins are responsible for reverse

cholesterol transport and play an important role in being a naturally occurring

potent anti-inflammatory and antioxidant agent with the protein moiety involved:

Apo A. It is the protein moiety of the lipoproteins that is modified by the

processes of oxidation, glycation, and glycoxidation with a resultant increase

in redox stress and the production of ROS. Furthermore, the modification of the

protein moiety is responsible for their retention within the intima, inducing

atherogenesis and thus atheroscleropathy. [69,70]

 

(L). Lipotoxicity – specific

 

Lipotoxicity is also associated with MS, IR, PD, and T2DM. Unger et al.[71-76]

feel this specific lipotoxicity is attributed to products of the excessive

non-beta- (non-mitochondrial) oxidative metabolism of FFA in the skeletal and

the myocardial muscle, the liver and the pancreatic islets.

 

In addition, these toxic metabolic products are thought to cause the

complications of MS, IR, PD, and T2DM by creating cellular dysfunction and, in

time, promoting programmed cellular death (lipoapoptosis). [74,75] In the normal

state, FFA delivery to non-adipose tissue is closely regulated to its need for

fuel. FFAs normally rise during exercise and fasting in order to meet metabolic

requirements and thus, homeostasis is maintained. However, as a result of

over-nutrition (western diet), the FFA influx may exceed FFA usage and FFA

non-beta oxidation ensues.

 

These non-mitochondrial FFA metabolites, which are responsible for injuring

cells, result in lipoapoptosis, include triglycerides, ceramide, and products of

lipid peroxidation. Ceramide (an amino alcohol with a LCACoA attached to the

amino group) has been implicated for some time in the apoptotic pathway of the

T1DM autoimmune destruction of beta cells by sphingomyelin degradation. [77]

 

Ceramide can be formed in these cells by direct de novo synthesis from FFAs.

[72] Ceramide is responsible for the induction and activation of NFkappa B. [78]

 

In the process of developing T2DM, only those beta cells with the highest fat

content give way to the ceramide cascade thus leaving enough functioning beta

cells to maintain insulin independence but not enough to compensate for the

co-existing insulin resistance with the subsequent development of impaired

glucose tolerance, impaired fasting glucose and the development of overt T2DM.

This entire process is magnified and progresses due to an intense redox

(oxidative stress within the islet and intima which incorporates and implicates

the multiplicative manifold A-FLIGHT toxicities).

 

I). Insulin toxicity

 

Insulin toxicity (hyperinsulinemia, hyperproinsulinemia, and hyperamylinemia) is

associated with MS, IR, PD, and early T2DM. In late T2DM as beta cell failure

develops there is no longer insulin toxicity. Insulin is known to up-regulate

the number of AT-1 receptors, activate the RAAS, and be capable of cross talking

with the AT-1 receptor. Recently, AT-1 receptors have been identified on the

islet beta cell and the islet endothelial cell.

 

Thus, hyperinsulinemia can be linked back to the section " (A). Angiotensin II "

with resultant increased redox stress systemically as well as within the intima

and islet as insulin, proinsulin and amylin are all three elevated within the

intima and islet milieu. [20-25]

 

Endogenous Hyperinsulinemia (eHI) is associated with MR, IR, PD, and early T2DM.

Additionally, eHI is associated with hypertension and atheroscleropathy

(coronary artery disease). eHI is also associated with elevated FFA, plasminogen

activator inhibitor-1 (PAI-1), elevated sympathetic tone and activity, increased

sodium and water reabsorption leading to volume expansion which leads to and

supports hypertension in the clustering phenomenon of MS relating to section

(H). Hypertension toxicity. Previously discussed, insulin, proinsulin, and

amylin have been noted to contribute to the elevation of Ang II with increases

in renin and aldosterone.

 

Amylin the fraternal twin of insulin has been shown to induce lipolysis which

elevates FFA and links to the sections on (F), (L), and (T). The reader will

note that the various sections within the A-FLIGHT toxicities interact and play

off one another creating a vicious cycle of promoting redox stress within the

intima and islet.

 

Additionally, it is important to note that increased proinsulin concentrations

predict death and morbidity caused by coronary heart disease independent of

other major cardiovascular risk factors. [79,80]

 

(I). Inflammation toxicity

 

A new insight into the study of atherosclerotic plaques has evolved over the

past decade and now the accepted role of inflammation in vulnerable plaque

pathology has been widely accepted in the field of atherosclerology.

 

Currently, chronic inflammation is gaining momentum as a prelude to MS, IR, PD,

and T2DM.

 

Increasingly, this quartet in the continuum of the natural history of diabetes

is being accepted by diabetologists and researchers as a chronic inflammatory

disease. [9,81-92]

 

The four " cardinal signs " of inflammation described by Aulus C. Celsus in De re

medicina in 30 A.D. are: rubor, calor, dolor, and tumor and currently there is a

large body of information that atherosclerotic vulnerable plaques (VP) fit the

above criteria.

 

Rubor

 

VPs have a unique increase in angiogenesis of the vasa vasorum which act as a

FedEx delivery system and thus increase flow for inflammatory cells and

injurious substrates to promote vulnerability at the endothelial extracellular

matrix interface.

 

Calor

 

Recently, these VPs have been shown to possess a higher core temperature.

 

Dolor

 

There is no direct pain associated with the VP, however, once it is ruptured the

cardiovascular event is quite painful and the fixed stenotic lesions of

atheroscleropathy create the painful syndrome of angina pectoris.

 

Tumor

 

There is no doubt that there is swelling of even the atheroma (outward positive

remodeling) as well as encroachment upon the lumen with negative remodeling

resulting in a stenotic lesion which entertains the fifth sign of inflammation,

functio laesa, inhibited or lost function. Recently, Naghavi M et al. were able

to show that these VPs were more acidic which may be an asset in detecting their

presence in vivo. [93-96] (figure 5)

 

Inflammation toxicity (with increased redox stress and cytokines) is associated

with MS, IR, PD, and early as well as late T2DM.

 

The innate inflammatory mediators, TNFalpha and interleukin 6 (IL-6), are

tightly associated with central (visceral – omental) obesity, MS, IR, PD, and

T2DM. [97][98,99] This innate immune system (IL-6 and TNF alpha which activates

the acute phase response) is more ancient and does not require a previous

antigenic stimulus as does theacquired antigen – antibody related immune system.

 

Downstream from IL-6 and TNFalpha, elevated white blood cell count, sialic acid,

orosomucoids and the acute phase reactants: highly sensitive C reactive protein

(hs-CRP), fibrinogen, and serum amyloid A are associated with the development of

T2DM and atheroscleropathy. Factor VIII, von Willebrand factor (indicating

endothelial cell activation) and activated partial thromboplastin time have also

been implicated in the development of T2DM. [100]

 

NFkappa B is associated with redox stress and the isoform inducible iNOS in the

apoptosis of the beta cell in both T1DM and T2DM. Both NFkappa B and TNFalpha

are induced by ROS [60].

 

The adhesion of the leukocytes to the post-capillary venule is an important step

in the inflammatory process and the adhesion of the leukocytes to the

endothelial cells is induced by ROS. This effect is abolished by catalase but

not SOD, suggesting that H2O2 and the OH- radical but not super oxide is

involved. ROS treatment of endothelial cells induce the focal adhesion kinase pp

125 PAK, a cytosolic tyrosine kinase which has been implicated in the

oxidant-mediated adhesion process. [101]

 

This section and the section (A). Ageing are closely related as ROS and RNS are

widely implicated in the inflammatory and ageing process. [102]

 

Recently, Syad MA, Pietropaolo M, and colleagues [103] published a paper

entitled: Is type 2 diabetes a chronic inflammatory / autoimmune disease? They

were able to detect a subset of patients with T2DM in which an acute phase

response seemed to be associated with islet cell autoimmunity. They were able to

demonstrate that 12 % of patients age 65 and older had islet cell autoantibodies

(ICA) and GAD. They also were able to detect a significant increase in

fibrinogen (P= 0.005) and C-reactive protein levels (P= 0.025) in patients with

high levels of GAD 65 and/or IA-2 autoantibodies as compared with antibody

negative patients and control subjects. [104]

 

This group of T2DM has been referred to by Zimmet and others as latent

autoimmune diabetes mellitus in adults (LADA) [105]

 

This information points to the presence of the acquired immune (humoral islet

cell autoimmunity) system being in play in a subset of older as well as younger

patients with T2DM and that this system is significantly associated with the

downstream acute phase reactants of the innate immune system: C-reactive protein

and fibrinogen. This same delicate interplay of the two immune systems may well

be in play in the development of atheroscleropathy as we know there are

autoantibodies to oxidized LDL-C. As further knowledge emerges regarding these

two immune systems and how they interact we may have an even better

understanding of the complex mechanism of MS, IR, PD, T2DM, and

atheroscleropathy.

 

The current medical literature has provided us with a growing body of knowledge

in studies of basic science, epidemiology, animal, and even human clinical

trials that implicate inflammation in the pathogenesis of MS, IR, PD, T2DM and

atheroscleropathy with their morbid, deadly intersection.

 

The above is information is incomplete and just a small portion of information

was presented to set the stage regarding the role of inflammation in the intima

and islet. In summary, there are two common threads that weave these two

diseases (T2DM and accelerated atherosclerosis) together, resulting in the

complex mosaic fabric of atheroscleropathy:

 

Redox stress and inflamation. (figure 6)

 

It is interesting to note that both HMG CoA Reductase inhibitors (statins) and

ACE inhibitors and ARBs are having such a profound effect on non diabetic

atherosclerosis and hypertension and an equal if not greater reduction in events

in the treatment of diabetic associated hypertension, atheroscleropathy, and

even delaying or preventing the development of overt T2DM. (table 9) Note that

the three drug classes all have a direct or indirect positive effect on

inflammation and redox stress. Utilizing the RAAS acronym may have a positive

effect on event outcomes at the morbid mortal intersection associated with the

interweaving threads of redox stress and inflammation which result in

atheroscleropathy.

 

(G). Glucotoxicity

 

Glucotoxicity is associated with both type 1 and type 2 diabetes mellitus and,

thus, the similarly shared multiple opathies associated strongly with redox

stress (figure 7). There is a major difference between T1DM and T2DM in regards

to atheroscleropathy. In T1DM the atheroscleropathy does not start until there

is a diagnosis and glucotoxicity develops acutely. In contrast T2DM is preceded

by 5–10 years of a MS, IR, and PD state consisting initially of postprandial

glucose elevations (IGT) then fasting glucose elevation.(IFG). Additionally, MS

and IR comes with the attendant A-FLIGHT toxicities. (table 3)

 

Four subsections are important in this discussion.

 

I. AGEs were discussed in section (A)

 

II. Autoxidative reactions

 

Autoxidative reactions occur as monosaccharides, and fructose-lysine can

spontaneously reduce molecular oxygen.

 

The reduced oxygen products formed are O2-, OH-, and H2O2. Each of these ROS can

contribute to damaging lipids and proteins through cross-linking and

fragmentation. [106-108]

 

The process of combined autoxidation and glycation is frequently referred to as

glycoxidation which is another common process of protein modification. The ROS

from these reactions serve not only as the source for autoxidation but also fuel

the cycle of AGE formation (ROS beget ROS).

 

Autoxidation occurs at the site of the protein component embedded within the LDL

cholesterol particle resulting in glycated LDL and glycoxidated LDL cholesterol

which contribute to its retention just as oxidized LDL is retained within the

intima which initiates and sustains atherogenesis and subsequent

atheroscleropathy.

 

Native LDL is not atherogenic and is not retained within the intima; however, if

it becomes modified by oxidation, glycation, glycoxidation or homocysteinated,

it becomes modified and retained (trapped to adjacent glycosaminoglycans and

structural glycoproteins) to initiate, maintain, and accelerate the atherogenic

process within the intima.

 

III. The Polyol – sorbitol pathway

 

The polyol – sorbitol pathway is also driven by an excess production of glucose.

Glucose is converted to sorbitol by aldose reductase at the expense of

NADH/NAD(P)H being converted to NAD+/NAD(P)+. Sorbitol is then converted to

fructose by sorbitol dehydrogenase at the expense of NAD+ NAD(P)+ being

converted to NADH/NAD(P)H. [60-62]

 

This reductive stress (pseudohypoxia) of the polyol – sorbitol pathway thus

amplifies the redox stress within the islet milieu. This singular pathway is of

great importance as it is the major pathway for supplying unpaired unstable

electrons through the process of reduction. This reductive stress is dependent

upon hyperglycemia associated with both T1DM and T2DM. Postprandial

hyperglycemia results in reductive stress even before overt T2DM has developed.

 

Were it not for the importance of this singular source of reductive stress, this

review could have been entitled " Intimal Oxidative Stress " .

 

IV. Glucose scavenging of nitric oxide

 

Endothelial dysfunction is strongly associated with both T1DM and T2DM. Brodsky

et al. have recently been able to demonstrate that glucose is capable of

directly scavenging NO resulting in the chemical inactivation of NO. They were

able to conclude that the glucose-mediated NO loss may directly contribute to

hypertension and endothelial dysfunction in diabetic patients. [109]

 

The authors were also able to show a glucose-mediated decline in the lifetime of

NO. These findings may have a direct, deleterious effect of decreasing the

naturally occurring antioxidant capability of NO.

 

Glucotoxicity increases oxidative stress as demonstrated by increased

8-hydroxy-2'-deoxyguanosine (8-OhdG, a marker for oxidative stress) found in the

urine and mononuclear cells from blood in T2DM patients.

 

Ihara et al. found higher levels of 8-OHdG and 4-hydroxy-2-nonenal-

(HNE)-modified proteins in pancreatic beta-cells of GK rats (a model of

non-obese type 2 diabetes) than in control Wistar rats. These levels increased

proportionally with age. [110]

 

Section " (F). Free Fatty Acids " would lead one to believe that a lipocentric

view is of extreme importance and may be playing the dominant role in beta cell

dysfunction and insulin resistance.

 

Poitout and Robertson [111] have recently pointed out (with strong supporting

data) that glucotoxicity is a prerequisite for lipotoxicity. They propose that

chronic hyperglycemia (independent of hyperlipidemia) is toxic for beta-cell

function, whereas chronic hyperlipidemia is deleterious only in the context of

concomitant hyperglycemia. With time, both glucotoxicity and lipotoxicity

contribute to the progressive deterioration of glucose homeostasis and beta cell

dysfunction. Seldom do either of these two toxicities exist alone in the

postprandial clinical setting of MS, IR, PD, and T2DM, and both contribute to

the excess redox stress associated with the other A-FLIGHT toxicities, having an

overall multiplicative effect within the intima and islet. [111]

 

Before leaving this section on glucotoxicity it is important to note that

cytosolic production of superoxide [O2'] results in the activation of protein

kinase C, increased formation of glucose-derived advanced glycation products,

and an increased flux through the polyol – sorbitol pathway. Nishikawa T et al

was able to show nicely that by blocking mitochondrial derived O2' with

manganese superoxide dismutase or uncoupling mitochondrial oxidative

phosphorylation they were able to prevent the above cytosolic perturbations.

[112] Additionally, Pennathur S et al were able to demonstrate in the

Cynomologus monkey that streptozotocin induced diabetes resulted in a hydroxyl

radical-like species which oxidized artery wall proteins. The oxidative

products, ortho-tyrosine and meta-tyrosine correlated strongly with serum levels

of glycated hemoglobin. In these early lesions 3-nitrotyrosine was not

correlated to the glycated hemoglobin. [113]

 

(H). Hypertension toxicity

 

Hypertension is associated with increased redox stress and ROS activity.

Furthermore, hypertension is associated with ROS mediated vascular damage and is

closely associated with the activation of Ang II (see section (A). Angiotensin

II) and its effect on the vascular NAD(P)H oxidase superoxide (O2-) generating

enzyme. [26]

 

Cellular sources of vascular superoxide production are the endothelial cell,

vascular smooth muscle cell and adventitial fibroblasts. The major enzymatic

sources are NAD(P)H oxidase, xanthine oxidase and, paradoxically, the eNOS

enzyme (in the presence of oxidative stress or deficiency of L-arginine or

tetrahydrobiopterin).[114]

 

It is important to note that glucotoxicity is closely associated with activation

of the RAAS at the local, interstitial and tissue levels.

 

Recently, amylin has been implicated as being elevated in patients who have a

positive family history associated with hypertension and is elevated prior to

the onset of hypertension when insulin remains at the normal level. Thus, amylin

levels may become a screening tool for the development of future essential

hypertension. [115]

 

Hypertension is associated with the clustering phenomenon of the metabolic

syndrome and its importance to the overall picture of redox stress is not to be

underestimated as it contributes significantly to the overall morbidity and

mortality associated with T2DM. [116,117]

 

(H). Homocysteine toxicity

 

The general population of diabetics (T1DM and T2DM) will, in all probability,

have the same amount of gene polymorphism of the folate-dependent methylene

tetrahydrofolate reductase gene with subsequent mild to moderate

hyperhomocysteinemia (hHcy) which occurs in 10–15% of the general population.

[118-120]

 

This gene polymorphism is especially important in those individuals with a

decrease in dietary folate. hHcy can be improved with folate supplementation and

can improve endothelial-dependent endothelial cell dysfunction. [121]

 

Homocysteine (Hcy) is not usually elevated as a direct result of diabetes unless

there is an associated development of impaired renal function. As nephropathy

develops, there is an associated elevation of total Hcy associated with a

decline in glomerular filtration rate. [122]

 

This plays an extremely important role for those diabetic patients on dialysis.

[123] hHcy is thought to induce an oxidative inactivation of endothelial nitric

oxide, in part by inhibiting or consuming the expression of cellular glutathione

peroxidase (GPx). In heterozygous cystathionine beta-synthase deficient -/+

mice, Weiss et al. were able to restore endothelial cell function by increasing

cellular thiol and reducing glutathione pools and increasing GPx activity with

restoration of the endothelial function. [124]

 

The ensuing cellular redox stress is magnified and total Hcy consumes NO by the

indirect process of O2- converting NO to toxic peroxynitrite (ONOO-).

 

In addition to ONOO- formation, NO in conjunction with thiols and oxygen

radicals generate nitrotyrosine and nitroarginine which compete for the

substrate eNOS in a feedback mechanism, limiting further NO generation.

[125-127] As a result, there is endothelial cell dysfunction, endothelial cell

toxicity and endothelial cell loss, increased ROS, increased ONOO- and decreased

NO associated with hHcy. [128] hHcy is multiplicative in nature and even though

its effects may occur later in T2DM than the other associated toxicities, it has

a devastating effect on endothelial cell function.

 

Presently, we know there are other toxicities operating within the renal

glomerulus producing microalbuminuria (reflecting endothelial cell dysfunction

and damage) at a stage prior to the declining glomerular filtration rate

responsible for hHcy.

 

A recent clinical study by Maejima et al.[129] revealed significant elevated

levels of ONOO- peroxynitrite (by Griess method) in 126 T2DM patients as

compared to 76 non-diabetic controls. ONOO- levels were related to the presence

of hypertension and advanced microvascular complications. In addition, ONOO-

correlated positively with elevations in AGEs and serum lipid peroxide.

 

These data support the hypothesis that decreased endothelium-dependent

vasodilatation in diabetic subjects is associated with the impaired action of NO

secondary to its consumption from redox stress rather than decreased NO

production from vascular endothelium. Clinically, abnormal NO metabolism is

related to advanced diabetic microvascular complications. Zhang et al.[130] were

able to demonstrate that increased concentrations of Hcy resulted in a decreased

NO response to bradykinin and L-arginine.

 

They were able to show that Hcy stimulated the formation of superoxide anions

and peroxynitrite with increased levels of nitrotyrosine. The addition of

5-methyltetrahydrofolate restored NO responses to bradykinin and L-arginine

agonists. In addition, scavengers of peroxynitrite and SOD mimetics reversed the

Hcy-induced suppression of NO production by endothelial cells. Concentrations of

Hcy greater than 20 ìM produced a significant indirect suppression of eNOS

activity without any discernible effects on its expression.

 

Li et al. just published an article showing an unexpected effect of Hcy-induced

oxidative stress resulting in an increase of 3-hydroxy-3-methylglutaryl coenzyme

A reductase in vascular endothelial cells, as well as decreasing endothelial NO.

 

They were also able to demonstrate that " statins " (Table 7) were able to

increase NO as well as decreasing cellular cholesterol. [131]

 

Stuhlinger MC et al were able to demonstrate that Hcy impairs the nitric oxide

synthase pathway. Homocysteine inhibits dimethylarginine dimethylaminohydrolase

(DDAH) which is responsible for degrading ADMA.

 

This effect of Hcy causes the endogenous inhibitor of nitric oxide synthase,

ADMA to accumulate and inhibit nitric oxide synthesis. This effect helps to

explain the deleterious effect of Hcy on the endothelial cells ability to

promote vasodilatation and associated endothelial cell dysfunction with

decreased NO synthesis. [132]

 

(T). Triglyceride toxicity

 

Multiple lipases (intestinal, muscular – both skeletal and cardiac-, adipose,

and hepatic) are responsible for the dynamic flux between the long chain fatty

acids (LCACoA esters) and the glycerol molecular backbone of the triglycerides

(see section (F). Free Fatty Acids " ).

 

Hypertriglyceridemia certainly plays a role in toxicity regarding the

development of redox stress, not only its role in lipotoxicity and FFA toxicity

discussed previously, but independently as its own marker of toxicity. There is

a close association of hypertriglyceridemia and the atherogenic small dense LDL

cholesterol particles which are more likely to be oxidized and contribute to

redox stress. This condition is central to the lipid triad [133].

 

We need to recall that Apo E is responsible for carrying this lipid fraction and

that the Apo E -/- knockout mouse develops atherosclerosis at an accelerated

rate. We need to also bear in mind that gene polymorphism may play a role in the

development of ADIA since Apo E is an important part of all amyloid formation

and stabilization. Kahn et al. were able to demonstrate in the human islet

amyloid polypeptide transgenic mouse model that these mice did not develop islet

amyloid unless fed a high fat diet [134].

 

Stored neutral triglycerides provide the substrate for FFA production which can

be immobilized immediately by exercise or stress induced lipolysis.

 

When these are stored in ectopic non-adipose cells such as the cardiac and

skeletal myocyte, the endothelial cell or the islet beta cell, they are capable

of causing cellular dysfunction or lipoapoptosis as discussed in the sections

" (F). Free fatty acids " and " (L). Lipotoxicity – Specific " .

 

As stated earlier in this paper, it is difficult to separate these three

moieties as they are closely interconnected with each other and within the

manifold A-FLIGHT toxicities.

 

Redox stress and matrix metalloproteinases

 

Elevated redox stress is associated with an increase in matrix metalloproteinase

(MMP) activity, especially the inducible MMP-9 [135].

 

This would be associated with an increase in extracellular matrix (ECM)

remodeling and would contribute to increased intima media thickness within the

arterial vessel wall. This would accelerate the process underlying the similar

mechanism of AGEs with a stiffening and decreased compliance of the arterial

vessel wall which would contribute to diastolic dysfunction of the arterial

vessel wall. The acceleration of the stiffness of the arterial vessel wall would

contribute to hypertension, specifically systolic hypertension. This mechanism

may be in play in the clustering of hypertension in the metabolic syndrome.

 

Cells are dependent on integrin matrix ligand binding sites and MMP-9 is a

basement membrane degrading enzyme. Cells are constantly re-establishing new

integrin matrix binding sites. However, if there is a complete disconnection of

integrin matrix binding sites due to a robust increase in MMP-9, the cell may

undergo apoptosis. MMP-9 was recently shown to be elevated in diabetes mellitus

and, in addition, the role of redox stress was shown to play an important role

[135].

 

A robust activation of MMP-9 may result in a complete disconnection of the beta

cell and the surrounding ECM with resultant apoptosis. Recently, in our

laboratory, we have been able to demonstrate decreased endothelial cell density

with increased apoptosis of endothelial cells in the hearts of mice treated with

alloxan vs. controls.

 

We were also able to show a decrease in NO and an increase in peroxynitrite and

ROS in these same animals thus, linking the importance of cellular apoptosis,

MMP-9 and redox stress. We then compared these findings of alloxan-induced

diabetes in MMP-9 knockout mice to alloxan-induced diabetes in the wild type.

Alloxan-induced diabetes MMP-9 -/- mice did not have induced apoptosis and did

not have a decrease in endothelial cell density when compared to wild type

alloxan-induced diabetes (unpublished data).

 

These findings may apply to the beta cell within the islet, as all cells require

an integrin matrix binding for survival. The MMP-9 may also decrease the larger

size amylin derived islet amyloid fibrils to the more intermediate size toxic

amyloid particles and contribute to apoptosis as described by Janson et al.[136]

(Table 5).

 

MMP-9 has also been shown to be elevated in laminitic horses having digestion of

the basement membranes with resultant separation of the epidermal and dermal

lamina. [137] These same processes within the islet could be responsible for a

loss of intracapillary endothelial cells which would decrease the rate at which

they could pick up newly synthesized insulin and transport it to the systemic

circulation, and provide a mechanism for the delay in first phase insulin

secretion which is typical of T2DM and even impaired glucose tolerance.

 

MMP-9 may even play a role in the clearing of ECM in order to allow for the

space-occupying lesion of ADIA deposition. Redox stress (signaling) activates

MMPs (Table 5).

 

 

Outline Conclusion

 

Abstract

Introduction

Conclusion

Abbreviations

Acknowledgment

References

 

 

Throughout this review, we have tried to remain focused on the relationship

between redox stress and ROS in the intima and at times the islet, and how these

two interact with the multiplicative effect of the A-FLIGHT toxicities of MS,

IR, PD, and overt T2DM to induce atheroscleropathy. The reader will note that

redox stress and ROS operate through similar mechanisms and will operate in a

similar fashion in other chronic disease states such as chronic inflammatory

diseases (pancreatitis, rheumatoid arthritis, ulcerative colitis, Crohn's),

ageing, cancer, ischemia/ischemia-reperfusion injury, hypertension,

diastolic/systolic dysfunction, congestive heart failure, diabetic and

nondiabetic nephropathy and neurodegenerative diseases.

 

When redox homeostasis transitions to redox stress, redox signaling ensues in

all tissues and organs regardless of the multiple similar or dissimilar

etiologies.

 

Redox stress is a redox signaling system. [101,138]

 

Reflections and future directions

 

An article entitled " Diabetes as a manifold disease " (previously published in

the February 8th, 1902 issue of JAMA) was reprinted in the February 13th, 2002

issue of JAMA, in the section on 100 years ago. [139,140]

 

T2DM and associated atheroscleropathy remain a heterogeneous and manifold

disease not only in their etiology but also in their manifold toxicities

associated with MS, IR, PD, and T2DM.

 

In 1902, the author (unknown) could not have envisioned the exponential growth

of T2DM and atheroscleropathy we are currently experiencing.

 

Just as this author pointed to a new concept, we have attempted, in this review,

to outline the important contemporary concept of intimal redox stress and the

rusting – rancid intima within vulnerable atherosclerotic plaques.

 

Treatment and potential prevention of these diseases can be accomplished through

global risk reduction of the manifold toxicities by using the currently

available treatment modalities we now have at our disposal. [141]

 

 

JoAnn Guest

mrsjoguest

DietaryTipsForHBP

http://www.geocities.com/mrsjoguest

 

 

 

 

 

 

 

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