Current Drug Targets - Cardiovascular & Hematological Disorders - Volume 4, Issue 1, 2004

The insulin resistance syndrome is described as a clinical syndrome in which there is clustering of insulin resistance together with factors such as hypertension, dyslipidemia and obesity leads to a substantial increase in cardiovascular risk. In the United States, almost one quarter of adult population is now believed to have this syndrome. Insulin resistance is a state of dysregulation of glucose-insulin homeostasis in which the ability of insulin to stimulate glucose uptake in peripheral tissues is reduced. Insulin resistance is a crucially important metabolic abnormality in type 2 diabetes, where coronary artery disease is the most significant cause of morbidity and mortality. Diagnosis of diabetes is thought to be preceded by a long term insulin resistance state, during which blood glucose level is maintained near normal levels by compensatory hyperinsulinemia. Cardiovascular risk is increased in this euglycemic prediabetic state, suggesting that insulin resistance per se is atherogenic. Insulin resistance has often been associated with the other known cardiovascular risk factors. Hyperinsulinemia induces hypertension, which may be caused by increased renal sodium retention, increased Na+-H+ exchange on vascular wall cells, or increased sympathetic activity. Hyperinsulinemia also induces abnormalities of lipid metabolism. In addition to this atherogenic proclivity, insulin itself may initiate vascular smooth muscle cell proliferation mediated by stimulating insulinlike growth factor receptors, leading to atherosclerosis. More recently, insulin resistance has been shown to be associated with the impairment of vascular endothelial function, which is believed to be an initial step toward atherosclerosis. In insulin resistant humans, there is evidence that the acetylcholine-induced coronary artery vasodilatory response is impaired. Acetylcholine stimulates the release of nitric oxide (NO) from endothelial cells and diffuses to the underlying smooth muscle cells to cause relaxation. Thus, impaired vascular relaxation in response to acetylcholine is thought to reflect endothelial dysfunction. Insulin resistance may be linked to endothelial dysfunction by a number of mechanisms, including disturbances of subcellular signaling pathways common to both insulin action and NO production, oxidant stress, endothelin, the reninangiotensin system and the secretion of hormones and cytokines. The long predrome of insulin resistance in the development of type 2 diabetes cause the vascular endothelium to be exposed to a potentially atherogenic environment for many years before the onset of coronary artery disease. In the near future, early intervention to improve insulin resistance will be a powerful therapeutic strategy to ameliorate coronary endothelial function, leading to prevention of coronary artery disease. The articles in this issue provide a valuable overview of insulin resistance, impaired coronary endothelial function and new paradigms for prevention of coronary artery disease based upon targeting the endothelial dysfunction in the molecular level as well as the clinical setting.

Dysfunction of the endothelium in large- and medium-sized arteries plays a central role in atherogenesis. The insulin resistance syndrome encompasses more than a subnormal response to insulinmediated glucose disposal. Patients with this syndrome also frequently display elevated blood pressure, hyperlipidemia, and dysfibinolysis, even without any clinically manifested alteration in plasma glucose concentrations. Of note endothelial dysfunction and atherosclerosis also have been demonstrated in patients with hypertension, which is one of the features of the syndrome of insulin resistance. Insulin-induced vasodilation, which is mediated by the release of nitric oxide (NO) release, is impaired in obese individuals who display insulin resistance. Although it is tempting to speculate that loss of endothelium-dependent vasodilation and increased vasoconstriction might be etiological factors of elevated blood pressure, the factors contributing to NO-mediated endothelial dysfunction in the insulin-resistant state are not fully defined. Experimental evidences suggest that (6R)-5,6,7,8-tetrahydrobiopterin (BH4), the natural and essential cofactor of NO synthases (NOS), plays a crucial role not only in increasing the rate of NO generation by NOS but also in controlling the formation of superoxide anion (O2 -) in the endothelial cells. Under insulin-resistant conditions where BH4 levels are suboptimal, in addition to a reduced synthesis of NO, an accelerated inactivation of NO by O2 - within the vascular wall was observed. Furthermore, oral supplementation of BH4 restored endothelial function and relieved oxidative tissue damage, through activation of eNOS in the aorta of insulin-resistant rats. These results indicate that abnormal pteridine metabolism contributes to causing endothelial dysfunction and the enhancement of vascular oxidative stress in the insulin-resistant state.

Increasing evidence has revealed that endothelial cells play an important role in the pathogenesis of development and progression of atherosclerosis. Endothelial dysfunction induces disruption of the balance between vasoconstrictive factors and vasodilatory factors secreted from endothelial cells. Among these factors, NO and angiotensin II are especially important factors, and have been shown to exert various direct effects on the endothelial functions that are closely related to the pathogenesis of atherosclerosis. Endothelial dysfunction induces decreased NO bioactivity and increased angiotensin II expression, which increase oxidative stress and expression of adhesion molecules, cytokines, and chemokines. These conditions mediate inflammation, proliferation, and thrombogenesis in vessel wall and promote atherosclerotic lesions. On the other hand, therapies that improve endothelial dysfunction, such as administration of HMG-CoA reductase inhibitors or angiotensin converting inhibitors, have been demonstrated to reduce cardiovascular events and strokes. In this article, we focus on NO and angiotensin II and describe their roles in the pathogenesis of atherosclerosis.

Coronary spasm plays an important role in the pathogenesis of not only variant angina but also coronary heart disease in general including acute coronary syndromes.The incidence of coronary spasm in Japanese patients with angina pectoris was about 40%.The total number of patients with angina pectoris increases with old age.The patients ' age distribution was relatively younger in the coronary spasm than in the stable effort angina.The vascular endothelium has been reported to be a multifunctional organ whose integrity is essential to normal vascular physiology,and whose dysfunction can be a critical factor in the pathogenesis of vascular disease.Acetylcholine and methacholine cause vasodilation by endothelium-derived relaxing factor when endothelium is functioning normal,whereas they cause vasoconstriction when endothelium is removed or damaged.Coronary spasm can be induced by acetylcholine and methacholine.The patients with coronary spasm may have a disturbance in the endothelial function of the coronary arteries.

Several intervention studies have shown that some hypolipidemic and hypotensive drugs such as fibrates,3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)reductase inhibitors,angiotensin converting enzyme (ACE)inhibitors and calcium (Ca)-antagonists prevent atherosclerosis.The main pathological findings in atherosclerosis include abnormal reactions of neutrophils,lymphocytes and monocytes / macrophages,vascular smooth muscle cells and vascular endothelial cells,and the accumulation of cholesterol ester in the arterial wall.Therefore,investigating the effects of these drugs on the arterial wall may improve understanding of the mechanisms underlying atherosclerosis.Here,based on recent studies including our own, we describe the relationships between risk factors for atherosclerosis,especially hyperlipidemia and hypertension,and the molecular mechanisms that govern lipid metabolism in the arteries.

Endothelial dysfunction is a feature of a variety of clinical states of insulin resistance,and increasingly it is recognized that pre-diabetic states of insulin resistance are associated not only with insulin resistance but with increased cardiovascular risk.The metabolic syndrome which typically accompanies insulin resistance brings aberrations in a number of classical cardiovascular risk factors,but it appears that insulin resistance itself represents an additional,non-classical risk factor.Therefore,the approach to treating the endothelium in patients with the metabolic syndrome might include therapies targeting insulin resistance. In this review,we provide a detailed overview of the current state of knowledge regarding the biguanide metformin and its effects on the endothelium.Its mode of action is reviewed,along with the available data from laboratory and experimental studies related to vascular function in animals and in humans.Metformin has beneficial effects on endothelial function which appear to be mediated through its effects to improve insulin resistance.Therapeutically targeting insulin resistance appears to be a viable route to improving endothelial function in clinical states of insulin resistance.

Microglia are currently accepted as sensor cells in the central nervous system that respond to injury and brain disease.The main function of microglia is believed to be brain defense,as they are known to scavenge invading microorganisms and dead cells,and also to act as immune or immunoeffector cells. However,microglia are also thought to contribute to the onset of or to exacerbate neuronal degeneration and / or inflammation in many brain diseases by producing deleterious factors including superoxide anions,nitric oxide and inflammatory cytokines.Nonetheless,microglia have also been shown to act neuroprotectively by eliminating excess excitotoxins in the extracellular space.Moreover,there is accumulating evidence that microglia produce neurotrophic and / or neuroprotective molecules;in particular,it has been suggested that they promote neuronal survival in cases of brain injury.In general,the question of whether microglia act as neurotoxic cells or as neuroprotective cells in vivo has gained much recent attention.In this paper,we provide a review of findings indicating that the microglia are basically neurotrophic / neuroprotective cells in the nervous system.In addition,the mechanism by which neurotrophic microglia become oriented to a neurotoxic state is discussed.

Phospholipases A 2 (PLA 2 )belong to a super-family of enzymes that hydrolyze membrane phospholipids at the sn -2 position to liberate free fatty acids and lysophospholipids.Different forms of PLA 2 are involved in inflammation,neurodegeneration,and intracellular and intercellular signaling related to neurotransmitter release,axonal growth and gene expression.The action of cytosolic PLA 2 (cPLA 2 )on phospholipid containing arachidonic acid at the sn -2 position releases arachidonic acid and lysophospholipids,precursors for various proinflammatory lipid mediators including prostaglandins, leukotrienes,thromboxanes,and platelet activating factor.During hypoxic / ischemic insults,alterations in calcium homeostasis and induction of cytokines results in stimulation of cPLA 2 and increased production of prostaglandins,leukotrienes,thromboxanes,and platelet activating factor.These metabolites cause atherosclerotic plaque development in cerebrovascular and coronary artery diseases in arterial walls and neuronal cell injury in brain tissue.Our studies on kainic acid-induced neurodegeneration in rat brain indicate that the stimulation of cPLA 2 increased generation of proinflammatory lipid mediators,and accumulation of 4- hydroxynonenal,a toxic aldehyde with neurodegenerative properties.Treatment of rat brain hippocampal slices with antimalarial drugs (non-specific cPLA 2 inhibitors),arachidonyl trifluoromethyl ketone (a specific cPLA 2 inhibitor),or surfactin (a non-specific cPLA 2 inhibitor)not only inhibits cPLA 2 activity but also blocks neurodegeneration suggesting that cPLA 2 inhibitors can be used as neuroprotective and anti- inflammatory agents in neurodegenerative diseases.

Aging,diabetes,and hypertension are conditions in which arterial and myocardial stiffness is increased.Increased arterial stiffness is manifested by an increased systolic arterial pressure,pulse pressure and pulse wave velocity,whereas increased myocardial stiffness is manifested by impaired left ventricular diastolic filling.Moreover,increased arterial stiffness increases cardiac workload,further aggravating already existing adverse changes in left ventricular structure and function.Indeed,studies in human beings have clearly shown that increased cardiovascular stiffness is a reliable predictor of cardiovascular morbidity and mortality. Increased cardiovascular stiffness is usually attributed to the development of fibrosis (i.e.,accumulation of collagen).It has also been recognized that the increased cardiac and vascular stiffness may be due to increased collagen cross-linking due to the formation of advanced glycosylation end-products (AGEs).In agreement with this notion is the finding that an inhibitor of AGEs formation improves vascular stiffness in diabetic rats.More recently,cross-link breakers have been developed,and the beneficial effects of one such agent (ALT-711)have been shown in experimental and clinical settings.This report briefly summarizes age related changes in cardiovascular structure and function and describes results of experimental and clinical studies involving collagen cross-link breakers.

Percutaneous transluminal coronary angioplasty has revolutionized the management of patients with coronary artery disease.Unfortunately,the procedure 's utility is limited by a frequent complication: restenosis.Coronary stenting prevents the elastic recoil and negative remodeling that can occur after angioplasty but,by inciting varying degrees of intimal expansion,it can also produce arterial renarrowing, known as in-stent restenosis (ISR).The precise mechanisms involved in the pathogenesis of ISR are incompletely understood.The recent introduction of drug-eluting stents (DESs)may help prevent ISR. However,DESs have not been universally successful,and they may introduce new complications that require further refinement.This review summarizes the current understanding of the pathogenesis of ISR and provides an objective overview of DESs.