Current Drug Targets - Cardiovascular & Haematological Disorders, Volume 4, Number 1, 2004
Contents
Hot
Topic Insulin Resistance and Impaired Coronary Endothelial Function
Guest
Editor: Teruo Inoue
Molecular Mechanisms of
Impaired Endothelial Function Associated with Insulin Resistance Pp. 1-11
Endothelial Dysfunction and
Coronary Atherosclerosis Pp.13-22
Endothelial Dysfunction and
Coronary Artery Spasm Pp.23-33
The Possible Therapeutic
Actions of Peroxisome Proliferator-Activated Receptor α (PPARα ) Agonists,
PPARγ Agonists, 3-Hydroxy-3- Methylglutaryl Coenzyme A (HMG-CoA) Reductase
Inhibitors, Angiotensin Converting Enzyme (ACE) Inhibitors and Calcium
(Ca)-Antagonists on Vascular Endothelial Cells Pp.35-52
Insulin Resistance as a
Therapeutic Target for Improved Endothelial Function: Metformin Pp.53-63
Microglia: Neuroprotective
and Neurotrophic Cells in the Central Nervous System Pp.65-84
Neuroprotection Abilities of
Cytosolic Phospholipase A2 Inhibitors in Kainic acid-induced Neurodegeneration Pp.85-96
Collagen Cross-link
Breakers: A Beginning of a New Era in the Treatment of Cardiovascular Changes
Associated with Aging, Diabetes, and Hypertension Pp.97-101
Current Understanding of
In-stent Restenosis and the Potential Benefit of Drug Eluting Stents Pp.103-117
[Back to top] Molecular Mechanisms of Impaired Endothelial Function
Associated with Insulin Resistance
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 insulin-mediated 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.
[Back to top] Endothelial Dysfunction and
Coronary Atherosclerosis
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.
[Back to top] Endothelial Dysfunction and
Coronary Artery Spasm
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.
[Back to top] The Possible Therapeutic Actions of Peroxisome
Proliferator-Activated Receptor α (PPARα ) Agonists, PPARγ Agonists,
3-Hydroxy-3- Methylglutaryl Coenzyme A (HMG-CoA) Reductase Inhibitors,
Angiotensin Converting Enzyme (ACE) Inhibitors and Calcium (Ca)-Antagonists on
Vascular Endothelial Cells
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.
[Back to top] Insulin Resistance as a Therapeutic Target for
Improved Endothelial Function: Metformin
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.
[Back to top] Microglia: Neuroprotective and Neurotrophic Cells in
the Central Nervous System
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.
[Back to top] Neuroprotection Abilities of Cytosolic Phospholipase
A2 Inhibitors in Kainic acid-induced Neurodegeneration
Phospholipases A2 (PLA2) 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 PLA2 are involved in inflammation, neurodegeneration, and intracellular and intercellular signaling related to neurotransmitter release, axonal growth and gene expression. The action of cytosolic PLA2 (cPLA2) 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 cPLA2 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 cPLA2 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 cPLA2 inhibitors), arachidonyl trifluoromethyl ketone (a specific cPLA2 inhibitor), or surfactin (a non-specific cPLA2 inhibitor) not only inhibits cPLA2 activity but also blocks neurodegeneration suggesting that cPLA2 inhibitors can be used as neuroprotective and anti-inflammatory agents in neurodegenerative diseases.
[Back to
top]
Collagen Cross-link Breakers: A Beginning of a New Era in the Treatment of
Cardiovascular Changes Associated with Aging, Diabetes, and Hypertension
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.
[Back to
top]
Current Understanding of In-stent Restenosis and the Potential Benefit of Drug
Eluting Stents
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.