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)

Abnormal growth of vascular smooth muscle (VSM) is seen in various pathologic conditions such as hypertension and atherosclerosis. Many classic vasoconstrictors have now been shown to be mitogenic, either by themselves or in conjunction with other cofactors, such as insulin. The mitogenic effects of vasoconstrictors may be due, in part, to activation of similar second messenger pathways, including stimulation of the Na+/H+ antiporter. It has been suggested, therefore, that an enhanced proliferation rate may be, in part, the consequence of elevated Na+/H+ exchange. This hypothesis is supported by several observations of the close association between Na+/H+ exchange activity and DNA synthesis in some cell types including fibroblasts and VSM. Stimulation of Na+/H+ exchange may play a permissive role in optimal growth by preventing H+ accumulation (a fall in intracellular pH [pHi]) due to the increased metabolic activity during cell stimulation. Enhancement of Na+/H+ exchange activity increases Na+ influx into the cell, and secondarily increases K+ entry through activation of Na+/K+ ATPase activity. Although the Na+/H+ antiporter may influence cell proliferation through various ionic mechanisms, it is not clear that enhanced proliferation is the consequence of overactivity of this antiporter. In VSM, there are also differences in the pattern of activation of the Na+/H+ antiporter by hyperplastic and hypertrophic agents. Although pHi is increased in response to both acute and chronic stimulation by hyperplastic factors, such as platelet-derived growth factor, a hypertrophic agonist such as angiotensin II increases pHi acutely but lowers it chronically. Likewise, hyperplastic factors increase the Na+/H+ antiporter (NHE-1) mRNA levels, whereas angiotensin II does not.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Na+/H+ exchange and vascular smooth muscle proliferation. 814 Nov 73

Endothelial cell integrity has been suggested to play a role in the development of atherosclerosis. The effects of fatty acids on endothelial barrier function were tested by measuring albumin transport across endothelial monolayers cultured on polycarbonate filters. Compared with control cultures, a 24-h exposure to 90 mumol/L lauric (12:0) and linoleic acid (18:2) but not to butyric (4:0), hexanoic (6:0), octanoic (8:0), decanoic (10:0), myristic (14:0), palmitic (16:0) or stearic acid (18:0) caused an increase in albumin transfer across endothelial monolayers. Selective enrichment of a "physiological" serum fatty acid mixture (FA-Mix; 90 mumol/L) with 90 mumol/L of 12:0 or 18:2 significantly increased albumin transfer, whereas enrichment with 90 mumol/L of 4:0, 16:0 or 18:0 significantly decreased albumin transfer relative to 180 mumol/L FA-Mix. Only 12:0- or 18:2-treated cultures showed increased Ca(++)-ATPase activity and the presence of lipid droplets. Fatty acids (60 mumol/L) extracted from butter fat and beef tallow had no effect on albumin transfer, whereas fatty acids extracted from chicken fat and corn oil consistently disrupted endothelial barrier function. This fat-induced disruption of endothelial barrier function seems to be related to the amount of 18:2 present in each fat source. These data indicate that unsaturated fats cause cellular perturbations that result in a decrease in endothelial barrier function in this model system, and that high dietary levels of unsaturated fats may be detrimental to cell integrity.
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PMID:Selective disruption of endothelial barrier function in culture by pure fatty acids and fatty acids derived from animal and plant fats. 832 May 62

For more than a decade, the inhibition of the renin-angiotensin system in heart failure has been regarded as pure vasodilator therapy. Consequently, the role of the renin-angiotension system has been seen as contributing to hemodynamic overload by vasoconstriction and volume retention. Meanwhile, clinical experience was indicated that important additional aspects of ACE-inhibition in heart failure are attenuation of the enhanced neuroendocrine activity and reversal or prevention of inappropriate trophic reactions of the overloaded myocardium. In overloaded hearts there is enhanced intracardiac formation of angiotensin due to enhanced expression of angiotensinogen and ACE, and due to accumulation of circulating, nephrogenic active renin. In human hearts, a mast-cell-derived chymase, which is not blocked by ACE-inhibition, contributes to intracardiac angiotensin formation. The enhanced intracardiac angiotensin-II formation in overloaded hearts is involved in coronary constriction, impairment of diastolic relaxation, myocyte enlargement and interstitial fibrosis, which aggravate the diastolic impairment. The major problem in overloaded, hypertrophied cardiocytes is the dedifferentiation with instabilization of Ca(++)-homeostasis due to an altered program of gene expression. Dedifferentiated cardiocytes have a reduced expression of sarcoplasmic reticulum Ca(++)-ATPase and an enhanced expression of the sarcolemmal Na+/Ca(++)-exchanger, resulting in an attenuation of active diastole (Ca(++)-reaccumulation into the sarcoplasmic reticulum), a depressed force-frequency relation, and an enhanced susceptibility for fatal arrhythmias. Furthermore, an enhanced local renin-angiotensin system in distensible coronary and systemic arteries seems to contribute to a reduced releasability of endothelium-derived relaxing factor, probably by reducing bradykinin availability. This modulation of endothelial function appears to contribute to the localization and progression of atheroma development in presence of risks factors for atherosclerosis.
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PMID:Pathophysiology of heart failure and the renin-angiotensin-system. 835 33

The cells within the vascular wall act as a unit regulating the contraction of smooth muscle cells. In arteries the endothelium and autonomic nerves provide the major factors that regulate intracellular calcium in smooth muscle cells, which determines contractile tone. The endothelium provides a major inhibitory influence, which itself is modulated by shear forces within the vascular lumen regulating endothelial cell calcium and the release of endothelium-derived relaxing factors. Of the major mechanisms controlling smooth muscle calcium, it has been suggested that voltage-dependent calcium channels are among the most important in mediating the inhibitory influence of the endothelium. Smooth muscle potassium channels and sodium-potassium adenosine triphosphatase (Na+,K(+)-ATPase) are important regulators of membrane potential, and each is affected by the endothelium. Because the activity of each hyperpolarizes the membrane potential, they counter the influence on voltage-dependent calcium channels and inhibit contraction. Both of these counterregulatory mechanisms have recently been shown to be impaired in diseased arteries. This may help to explain the diminished effectiveness of the endothelium on the smooth muscle. Thus, vascular disease may cause diminished release, increased destruction, or limited effectiveness of endothelium-derived relaxing factors. The failure of the inhibitory influence of the endothelium may be the principal mechanism by which vascular risk factors and disease increase vasoconstrictor tone, possibly contributing to hypertension and the progression of atherosclerosis.
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PMID:Pathways controlling healthy and diseased arterial smooth muscle. 837

Both atherosclerotic lesions and hypoxia alter the contractile properties of the arterial wall and, in particular, may interfere with the relaxation mechanisms dependent or not on the endothelium. The present study was designed to test the effect of severe hypoxia on the contractile behavior of the atherosclerotic rabbit aorta. Segments of aortas obtained from control, cholesterol-fed, or Watanabe hereditary hyperlipidemic rabbits were mounted in organ chambers for isometric tension recording. A change of the bath PO2 from "normoxic" conditions (95% O2-5% CO2) to "hypoxic" conditions (95% N2-5% CO2) caused relaxation in the precontracted control aortas (by approximately 85%) but a transient contraction (approximately 20% of the maximal contraction obtained with 30 mM KCl) followed by a relaxation in the precontracted atherosclerotic aortas. Both types of responses were observed in aortas contracted with aggregating platelets, 5-hydroxytryptamine (5-HT), norepinephrine, endothelin, and prostaglandin F2 alpha. The hypoxic contractions in atherosclerosis were not dependent on the presence of an intact endothelium. They could not be antagonized by blockers of alpha-adrenoceptors, 5-HT2 receptors, histamine receptors, thromboxane receptors, and muscarinic cholinoreceptors. Inhibitors of cyclooxygenase, lipoxygenase, Na+, K(+)-ATPase, and free radical scavengers or an activator of endothelium-derived relaxing factor did not significantly affect the hypoxic contraction; the absence of effect of some inhibitors of protein synthesis seems to rule out the involvement of endothelin, angiotensin II, and bradykinin. The hypoxic contraction was not influenced by omission of Ca2+ from the medium or by inhibition of Ca2+ influx but was prevented by blockade of intracellular Ca2+. The inhibitor of nitric oxide synthase (nitro-L-arginine, 100 microM) and the guanylyl cyclase inhibitor (methylene blue, 10 microM) both enhanced the initial contractile responses to 5-HT to a similar extent as hypoxia and completely prevented the hypoxic contraction in the atherosclerotic tissues. The cyclic nucleotide analogues 8-bromo-cGMP and dibutyryl cAMP also inhibited the hypoxic contraction in the atherosclerotic aorta. The cGMP levels were markedly decreased and the cAMP levels were moderately decreased in the aortas of the cholesterol-fed rabbits as compared with the control aortas. Hypoxia further decreased cGMP but not the cAMP levels in atherosclerotic aortas with and without endothelium. Our data thus demonstrate the occurrence of an unusual vasoconstrictor response in atherosclerotic arteries; this constrictor response depends on the availability of intracellular Ca2+ and seems to be due to the further inhibition of an already impaired cGMP production.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Hypoxia causes an abnormal contractile response in the atherosclerotic rabbit aorta. Implication of reduced nitric oxide and cGMP production. 838 23

Endothelial cells play a pivotal role in the development of atherosclerosis. An 'activated' phenotype of these cells is manifested by signal transduction-dependent expression of genes encoding cytokines, pro- and anticoagulant factors, and cell adhesion molecules. In the current study we examined the effect of ouabain, an inhibitor of Na+/K(+)-ATPase, on the process of endothelial cell activation. We demonstrated that ouabain was able to stimulate VCAM-1 expression and potentiate the effect of IFN-gamma on this process. Moreover, ouabain provided a complementary signal for either TNF or IFN-gamma in inducing iNOS expression. Our data also show, for the first time, that inhibition of Na+/K(+)-ATPase led to activation of the transcription factor, NF-kappa B, which may provide an explanation for the effects of ouabain on endothelial cells.
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PMID:Stimulatory effect of ouabain on VCAM-1 and iNOS expression in murine endothelial cells: involvement of NF-kappa B. 854 10

Intimal cells play an important role in the biology of the vascular wall. Variability in the metabolic activity of intimal smooth muscle cells (SMC), as well as the differential expression of cellular cytoskeletal proteins depend on factors such as degree of differentiation, aging, atherosclerosis, etc. Myosin ATPase activity and cytoskeletal proteins were studied in the intima of bovine femoral arteries and veins of mature animals. In some arteries the intima was thickened and two distinct layers--inner elastic hyperplastic (EHL) and outer, musculo-elastic (MEL) were observed. ATPase activity was well defined in endothelial cells (EC) as well as in SMC. However, differential enzymatic expression was observed in thickened intimas. SMC in the EHL were ATPase negative, while in the MEL they were ATPase positive. All EC and SMC in the "normal" intimas were vimentin positive, desmin and cytokeratin negative. In vessels with thickened intimas, the EHL showed intensive vimentin positivity; in the MEL desmin immunoreactive SMC were numerous as were as those in the media. Vimentin-positive SMC occupied their innermost part. Differences in the expression of ATPase activity and cytoskeletal proteins is discussed in terms of possible migration of medial SMC and/or morphological modulation observed in vessels with altered vascular walls.
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PMID:Expression of cytoskeletal proteins and ATPase activity in bovine femoral artery and vein intima. 886 55

The purpose of this study was to explore the effect of ischemia on the Na(+)-K(+)-ATPase activity and ouabain receptor of the myocardial sarcolemma in hypercholesterolemic rabbits. Male New Zealand white rabbits were fed with either standard chow or standard chow supplemented with 0.5% (w/w) cholesterol and 10% (w/w) coconut oil. After an 8 week feeding period, the rabbits underwent a thoracotomy and myocardial ischemia was induced by occlusion of the coronary artery. Myocardial samples from the ischemic and non-ischemic regions of the left ventricle of control and cholesterol-fed rabbits were taken for study. The cholesterol-fed group showed a decrease in both Na(+)-K(+)-ATPase activity and [3H]ouabain binding sites as compared to the control group. Ischemia caused a reduction in both Na(+)-K(+)-ATPase activity [3H]ouabain bindings sites in both control and cholesterol-fed rabbits. The combination of ischemia and hypercholesterolemia produced an additive effect, with a further decrease in both Na(+)-K(+)-ATPase activity and [3H]ouabain binding sites. Neither the activity of Mg+(+)-ATPase nor the binding affinity for [3H]ouabain was affected by either hypercholesterolemia or ischemia. These findings indicate that hypercholesterolemia may exaggerate certain aspects of functional deterioration arising during myocardial ischemia.
Atherosclerosis 1996 Nov 15
PMID:Ischemia-induced alteration of myocardial Na(+)-K(+)-ATPase activity and ouabain binding sites in hypercholesterolemic rabbits. 900 5

1. Metabolic disorders, such as obesity and non-insulin-dependent diabetes mellitus, and cardiovascular disorders, such as essential hypertension, congestive cardiac failure and atherosclerosis, have two features in common, namely relative resistance to insulin-mediated glucose uptake and vascular endothelial dysfunction. 2. Significant increases in limb blood flow occur in response to systemic hyperinsulinaemia, although there is marked variation in the results due to a number of confounding factors, including activation of the sympathetic nervous system. Local hyperinsulinaemia has a less marked vasodilator action despite similar plasma concentrations, but this can be augmented by co-infusing D-glucose. 3. Insulin may stimulate endothelial nitric oxide production or may act directly on vascular smooth muscle via stimulation of the Na+-H+ exchanger and Na+/K+-ATPase, leading to hyperpolarization of the cell membrane and consequent closure of voltage-gated Ca2+ channels. 4. There is evidence both for and against the existence of a functional relationship between insulin-mediated glucose uptake (insulin sensitivity) and insulin-mediated vasodilation (which can be regarded as a surrogate measure for endothelial function). 5. If substrate delivery is the rate-limiting step for insulin-mediated glucose uptake (in other words, if skeletal muscle blood flow is a determinant of glucose uptake), then endothelial dysfunction, resulting in a relative inability of mediators, including insulin, to stimulate muscle blood flow, may be the underlying mechanism accounting for the association of atherosclerosis and other cardiovascular disorders with insulin resistance. 6. Glucose uptake may determine peripheral blood flow via stimulation of ATP-dependent ion pumps with consequent vasorelaxation. 7. A 'third factor' may cause both insulin resistance and endothelial dysfunction in cardiovascular disease. Candidates include skeletal muscle fibre type and capillary density, distribution of adiposity and endogenous corticosteroid production. 8. A complex interaction between endothelial dysfunction, abnormal skeletal muscle blood flow and reduced insulin-mediated glucose uptake may be central to the link between insulin resistance, blood pressure, impaired glucose tolerance and the risk of cardiovascular disease. An understanding of the primary mechanisms resulting in these phenotypes may reveal new therapeutic targets in metabolic and cardiovascular disease.
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PMID:Insulin as a vascular hormone: implications for the pathophysiology of cardiovascular disease. 959 May 66

Although oxidants such as superoxide (O2.) and hydrogen peroxide (H2O2) play a role in host-mediated destruction of foreign pathogens yet excessive generation of oxidants may lead to a variety of pathological complications in the cardiovascular system. An important mechanism by which oxidants cause dysfunction of the cardiovascular system appears to be due to the increase in intracellular free Ca2+ concentration. Oxidants cause cellular Ca2+ mobilization by modulating activities of a variety of regulators such as Na+/H+ and Na+/Ca2+ exchangers, Na+/K+ ATPase and Ca2+ ATPase and Ca2+ channels that are associated with Ca2+ transport in the plasma membrane and the sarco(endo)plasmic reticular membrane of myocardial cells. Recent research have suggested that the increase in Ca2+ level by oxidants plays a pivotal role in inducing several protein kinases such as protein kinase C, tyrosine kinase and mitogen activated protein kinases. Oxidant-mediated alteration of different signal transduction systems and their interations eventually regulate a variety of pathological conditions such as atherosclerosis, apoptosis and necrosis in the myocardium.
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PMID:Targets of oxidative stress in cardiovascular system. 978 37


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