Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During the last decade, a multitude of experimental arguments have led to the concept that EDRF is nitric oxide (NO), a messenger not only involved in the control of vasomotor tone but also in vascular homeostasis, neuronal and immunological functions. Regardless of its origin, endogenous NO is produced through the conversion of L-arginine to L-citrulline by NO-synthase (NOS) from which several isoforms have recently been isolated, purified and cloned. NOS-type I (isolated from brain) and type III (isolated from endothelial cells) are termed "constitutive-NOS" and produce picomolar levels of NO from which only a small fraction elicits physiological responses. These isoforms are regulated by Ca(2+)-calmodulin with NADPH, FAD/FMN and tetrahydrobiopterin as co-factors and reveal a high degree of homology with the amino-acid sequence of cytochrome P450 reductase within the C-terminal domain. Functionally, neuronal-NOS type I is important in neurotransmission (modulation of NMDA receptor), the central control of vascular homeostasis and possibly learning and memory. In the peripheral nervous system, NOS appears to be linked to nonadrenergic noncholinergic (NANC) neuronal pathways. Endothelial-NOS type III is essential for the control of vascular tone in response to the release of endogenous mediators, although shear stress is the major trigger of endothelial-NOS activity under physiological conditions. NOS-type III also contributes to the prevention of abnormal platelet aggregation. NOS-types II and IV (isolated from macrophages) are Ca(2+)-calmodulin independent and are termed "inducible-NOS" since their activation is only promoted under pathophysiological situations where macrophages exert cytotoxic effects in response to cytokines. In contrast with NOS-types I and III, activation of NOS-type II in these cells induces the formation of nanomolar levels of NO which act as a defense mechanism of the immune system. Dysfunctions of the L-arginine-NO pathway have been characterized in multiple diseases (atherosclerosis, hypertension, diabetes, sepsis, cerebral ischemia, etc) and the design of more selective activators/inhibitors of NOS isoforms is a new challenge for the understanding of their pathophysiology and treatment.
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PMID:Nitric oxide: an ubiquitous messenger. 829 80

Endothelium-derived vasoactive factors are produced by the endothelium activated by effective stimulus, and with paracrine regulatory activity of the tone/proliferation of the vascular smooth muscle and platelet function. They are divided in two groups: endothelium-derived relaxing and contracting factors. Among the endothelium-derived relaxing factors, PG I2, EDRF (NO or other nitrous compound) and EDHF (still unidentified) have been considered Synthetized by the endothelium after stimulation by plasmatic, platelet-derived and endothelium-derived substances and mechanisms, towards the vascular smooth muscle (myorelaxing/cytostatic) and the platelets (antiaggregation). The endothelium-derived contracting factors include the EDCF1 (endothelins, 21 amino acids peptides), EDCF2 (O2-) and TxA2. Its production, induced by stimulus similar to those for relaxing factors, promotes constriction/mitogenesis of the vascular smooth muscle and platelet aggregation. Probably, endothelin-1 has indirect actions over hormonal mechanisms of cardiovascular and renal regulation. The vascular system establishes a tight regulation over the production of these endothelium-derived vasoactive factors. Its loss (usually due to alteration of endothelial responsiveness to stimulation) allows local or generalized modifications of the vascular tone. These can depend on hypertension, atherosclerosis, ischemia-reperfusion lesion, diabetes, inflammation and situations of farmacotoxicity (all developing vasoconstriction/vasospasm) or by septicemia (leading to vasodilation). This disregulation is also involved in the pathogenesis of hypertension, atherosclerosis and ischemia-reperfusion. The vascular tone regulation by endothelium also leads to systemic consequences. Essentially by decreasing cardiac, cerebral and renal blood flow it implies morphologic and functional modifications of these organs.
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PMID:[Vasoactive endothelial factors]. 833 93

Recently, atherosclerosis has become a matter of great concern because of a rapid increase of aged people. It has been widely known that omega-3 polyunsaturated fatty acids, rich in marine fish oil, have an antiatherogenic action. The mechanism is ascribed to its action on serum lipids, functions of the platelets, endothelial cells, smooth muscle cells and macrophages, prostaglandin and leukotriene metabolism, growth factor and cytokine production, EDRF production, blood pressure, etc. In this paper the basic and clinical evidences concerning the effects of fish oil on these multifactors, which are deeply involved in the development of atherosclerosis are reviewed.
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PMID:[Antiatherogenic action of omega-3 polyunsaturated fatty acids]. 841 64

Endothelium-derived relaxing factor/nitric oxide (EDRF/NO) is produced by the vascular wall and is a key modulator of vascular tone and blood pressure. NO is also produced by vascular smooth muscle (VSMC) where it can inhibit proliferation. Since cytokine-activated VSMC proliferation is a major event in the development of atherosclerosis, we investigated the influence of cholesterol (CE)-enrichment of VSMC on cytokine-induced NO synthesis. Treatment of VSMC with native LDL for one week did not promote CE-accretion or alter NO production following exposure to endotoxin (LPS). In contrast, CE-enrichment by cationized LDL augmented LPS-induction of NO synthesis 2-5-fold. While TNF-alpha promoted little NO synthesis in control VSMC, it was very potent after CE-enrichment. Similarly, CE-enrichment augmented IL-1 alpha-induced NO synthesis. However, CE-enrichment did not affect the synergistic induction of NO synthesis by cytokines in combination with IFN-gamma. Our findings suggest that CE-enrichment of VSMC upregulates signal transduction pathways which mediate cytokine and LPS induction of NO synthase activity.
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PMID:Cholesterol enrichment of arterial smooth muscle cells upregulates cytokine-induced nitric oxide synthesis. 844 15

In the autopsy material of 2932 men and 3051 women the frequency of fresh myocardial infarct and the severity of coronary atherosclerosis were highly significantly lower in the population suffering from malignancies than in that free of cancer. Lower frequency of myocardial infarct seems to result from lower severity of coronary atherosclerosis. The incidence rate of myocardial infarct was also significantly lower in the cancer--bearing group when both compared populations showed identical, severe (grade 4) coronary atherosclerosis. This observation seems to indicate lesser contribution of coronary spasm in cancerous population and justifies the discussion of possible significance of EDRF (endothelium-derived relaxing factor) and catecholamines.
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PMID:Relation between cardiovascular pathologic conditions and malignant tumours as seen by pathologist. II. Myocardial infarct and coronary atherosclerosis in the population suffering from malignant neoplasm as seen by pathologist. 848 83

Many cell types in myocardial tissue, including cardiocytes, contain receptors for angiotensin-II, but the activation of these receptors requires angiotensin concentrations in the micromolar range, which do not occur in plasma in vivo. However, angiotensins formed locally in the heart can activate these receptors in a paracrine and autocrine mode. In cardiac hypertrophy due to hemodynamic overload, the myocardial angiotensin formation is enhanced due to an augmented expression of angiotensinogen and ACE. Though the mRNA for prorenin is expressed in myocardium, the formation of active renin within the heart has not yet been demonstrated and myocardial renin activity is mainly due to contamination from circulating active renin. Intracoronary application of ACE inhibitors in hypertrophied hearts in vivo and in vitro indicates that the locally formed angiotensin-II contributes to coronary constriction, impairment of diastolic relaxation and marginally to the maintenance of systolic tension development. Angiotensin-II can exert trophic effects on cardiocytes and cardiac fibroblasts, and chronic inhibition of the cardiac RAS by ACE-inhibitors or AT receptor antagonists can induce partial regression of overload hypertrophy, even without normalizing the overload. This anti-trophic action may be partially due to the impairment of the angiotensin axis, but also due to enhancement of bradykinin availability, which results in an augmented release of endothelial anti-trophic signals such as EDRF/NO and prostacyclin. Preliminary evidence is compatible with the hypothesis that an activated local RAS in elastic arteries contributes to the localization and progression of atherosclerosis by suppressing EDRF releasability. However, the anti-atherosclerotic potential of ACE inhibitors and AT receptor antagonists in humans is still unknown.
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PMID:The cardiac renin-angiotensin system: physiological relevance and pharmacological modulation. 851 37

The endothelium can respond to a local environment by releasing a variety of substances that regulate the level of vascular tone. One of the most important of these vasoregulatory substances is EDRF. The function of the endothelium is altered in a variety of pathologic and physiologic conditions. This review focused on the role of risk factors for atherosclerosis as it relates to EDRF. Atherosclerotic blood vessels respond abnormally on exposure to stimuli that release EDRF. It is now also apparent that this abnormal vascular response may precede the development of significant atherosclerosis and that normalization of the EDRF response with treatment is possible. Thus abnormal endothelium-dependent relaxation has been demonstrated in hypercholesterolemic patients with little or no evidence of coronary angiographic disease and in patients with hypertension before the development of atherosclerosis. The interaction between risk factors and the function of the vascular endothelium with development of atherosclerosis may become a useful focus for therapies that benefit patient outcomes.
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PMID:Atherosclerosis: risk factors and the vascular endothelium. 857 37

In this chapter, we have briefly reviewed the current scientific knowledge of the role of vitamin C in the prevention of atherosclerosis and its associated clinical manifestations. There is good evidence from animal studies that vitamin C can slow the progression of experimental atherosclerosis. Most of these studies, however, were done either in guinea pigs, using ascorbic acid depletion, or in cholesterol-fed rabbits, using ascorbic acid supplementation. Both animal models have limitations, as guinea pigs are not a well-established (nor well-studied) model of atherosclerosis, and rabbits develop atherosclerosis at high serum beta-VLDL cholesterol levels, and in addition can synthesize ascorbic acid. In contrast, humans develop atherosclerosis spontaneously and readily at moderately elevated serum LDL cholesterol levels and have lost the ability to synthesize ascorbic acid. Thus, the animal studies discussed, although quite promising and suggestive of an anti-atherogenic effect of ascorbic acid, need to be expanded to primates before more definitive conclusions can be drawn. Similar to the animal data, the current evidence from epidemiological studies on the role of vitamin C in the prevention of CVD is inconclusive, with some studies showing a very strong correlation between increased vitamin C intake and incidence of CVD events and other studies showing no correlation at all. Studies on CVD risk factors indicate that vitamin C may moderately decrease total serum cholesterol levels, increase HDL levels, and exert a hypotensive effect. These findings are particularly intriguing and should be pursued vigorously in basic research studies to elucidate biological mechanisms. In addition, it appears that large placebo-controlled, double-blind, randomized trials of vitamin C supplementation (without simultaneous supplementation with vitamin E) in populations with a wide range of vitamin C body levels are needed in order to confirm or refute a role for vitamin C in the prevention of CVD. Unfortunately, no such trials are currently being conducted. The possible mechanisms by which ascorbic acid may affect the development of atherosclerosis and the onset of acute coronary events include effects on arterial wall integrity related to biosynthesis of collagen and GAGs, altered cholesterol metabolism mediated by vitamin C-dependent conversion of cholesterol to bile acids, and effects on triglyceride levels via modulation of lipoprotein lipase activity. A particularly intriguing possible mechanism for the anti-atherogenic effect of vitamin C is prevention of atherogenic, oxidative modification of LDL. Numerous in vitro studies have demonstrated that ascorbic acid strongly inhibits LDL oxidation by a variety of mechanisms. The potential effects of ascorbic acid on platelet function and EDRF metabolism are particularly intriguing, as they might have widespread consequences for the prevention of atherosclerotic lesion development as well as acute clinical events. Thus, both metabolic and antioxidant functions may contribute to the possible reduction of CVD risk by vitamin C.
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PMID:Ascorbic acid and atherosclerotic cardiovascular disease. 882 82

Since the classical studies by Furchgott and Zawadski (Nature, 1980, 286, 373-376), the vascular endothelium is known to play a fundamental role in the regulation of haemostasis and vasomotor activity. This is primarily due to its strategic interface position between the circulating blood and smooth muscle cells of the media. Due to the presence of specific receptors to mediators released during platelet aggregation (thrombin, ATP, serotonin, PAF, etc.), and the presence of mechanoreceptors sensitive to shearing forces generated by blood flow along the vessel wall, the endothelium is able to release, at the two poles of the cell, vasodilator and antiaggregant substances called "endothelium derived relaxing factors" (EDRFs), the best known for which are nitric oxide (NO) ans prostacyclin (PGl2). In the absence of endothelium (angioplasty), or in the case of endothelium dysfunction related to cardiovascular diseases such as hypertension, heart failure, atherosclerosis or diabetes, EDRF synthesis is absent or defective and its oxidative catabolism in increased (particularity by superoxide anion), resulting in varying degrees of disorders of haemostasis (thrombosis) and/or arterial and venous vasomotor activity. The only known effective treatment to palliate these dysfunctions is exogenous NO, supplied in the form of nitrate (nitroglycerin, isosorbide dinitrate, 5-mononitrate) or "NO donors" (Sin1, nitroprussate). The advantage of these substances is that their vasodilator effects (and, in some cases, their antiaggregant effects) are strictly endothelium-independent and they remain effective regardless of the causes and severity of endothelial dysfunction.
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PMID:[Nitrates and coronary vascular endothelium dysfunction]. 945 72

In 1980, Furchgott and Zawadski demonstrated that arterial smooth muscle cell relaxation in response to acetylcholine was dependent on the anatomical integrity of the endothelium. They baptized the principle responsible for this intercellular relationship EDRF (Endothelium Derived Relaxing Factor). EDRF was identified 7 years later to be a gaseous free radical: nitric oxide (NO). Many substances, such as bradykinin, histamine, serotonin, acetylcholine and exert their vasodilator effect by stimulating the endothelial production of NO. However, the most powerful stimulus of NO production by the endothelium is currently considered to be the shearing forces of the blood on the endothelium. The vasodilatation produced in response to an increased blood flow (flow-dependent vasodilatation) is therefore added to the local vasodilatation of metabolic origin. NO can therefore be considered to be an "endogenous nitrate", generated locally by the endothelium and exerting an essentially paracrine action (relaxation of adjacent smooth muscle cells, but also inhibition of platelet aggregation). Many clinical studies have demonstrated the existence of abnormalities of endothelium-dependent vasodilatation in atherosclerosis. While acetylcholine infusion induces vasodilatation in a healthy coronary artery it induces vasoconstriction in an atherosclerotic coronary artery. While a reduction of NO generation and/or its activity could be an important element of the physiology of atherosclerosis, excess NO production is largely responsible for the hypotension of septic shock.
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PMID:[Nitric oxide and circulatory homeostasis]. 945 76


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