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)

A role for angiotensin II (Ang II) in the pathogenesis of hypertension and atherosclerosis was studied using cultured vascular smooth muscle cells from spontaneously hypertensive rats. Chronic exposure of vascular smooth muscle cells, cultured in the presence of 1% plasma-derived serum, to Ang II resulted in a dose-dependent stimulation in growth and incorporation of radiolabeled matrix precursors into extracellular matrix-associated glycoconjugate material. The hormone also stimulated the incorporation of [3H]glycine into extracellular matrix glycoproteins and proteoglycans synthesized by cultures rendered quiescent by maintenance on serum-free medium for 48 h prior to exposure to Ang II. This was negated in the presence of saralasin. In quiescent cultures, a single exposure to angiotensin induced a rapid induction of mRNA coding for the extracellular matrix glycoprotein thrombospondin. Similar results were obtained with cells maintained on medium containing 1% plasma-derived serum; however, the levels of induction were reduced by this procedure. This study demonstrated that Ang II was capable of stimulating both growth and matrix elaboration by cultured vascular smooth muscle cells. These observations are indicative of a pathophysiological role for the vasoconstrictor peptide, which may contribute significantly to the development of hypertension.
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PMID:Modulation of extracellular matrix by angiotensin II: stimulated glycoconjugate synthesis and growth in vascular smooth muscle cells. 170 26

Endothelin (ET), a peptide originally isolated from the supernatants of cultured endothelial cells, exerts a wide variety of biological effects in different tissues. Endothelial-cell-synthesized ET-1 has been proposed to act in a paracrine manner on adjacent smooth muscle cells (SMC) in vivo, with effects that include both vascular reactivity (vasodilation/vasoconstriction) and mitogenesis. This study, by the use of immunocytochemically characterized SMC (rVSMC) isolated from the aortas of spontaneously hypertensive rats, has investigated a possible autocrine role for ET in regulation of the vasculature. Although quiescent cultures of rVSMC apparently did not constitutively express prepro ET-1mRNA, ET-specific transcripts could be induced by a variety of growth factors (transforming growth factor beta [TGF-beta]; platelet-derived growth factor-AA homodimer [PDGF-A chain]) and vasoactive hormones (angiotensin II [Ang II], arginine-vasopressin, and ET-1 itself). The kinetics for prepro ET-1mRNA induction in rVSMC were characteristically rapid in onset and transient. Down-regulation of protein kinase C by 48 h pretreatment of rVSMC with phorbol ester markedly reduced the subsequent ability of rVSMC to express ET-1 transcripts and secrete ET-1 peptide in response to Ang II. Inducible prepro ET-1mRNA expression was accompanied by a cycloheximide-inhibitable release of ET-1 peptide into the medium of rVSMC. ET-1 peptide was determined by both radioreceptor- and radioimmunoassay. Stimulated rVSMC accumulated ET-1 (approximately 200 pg.10(6) cells-1 x 4 h-1) at levels that attained biological relevance (approximately 10(-10) M). Sep-pak C18 extracts of medium from stimulated rVSMC elicited contraction of isolated endothelium-denuded rat mesenteric resistance vessels, and this response was characteristically protracted and difficult to "wash out." Synthetic (porcine) ET-1 promoted the expression of transcripts for PDGF-A chain, TGF-beta, and thrombospondin in quiescent rVSMC. Such effects of ET-1 on gene expression may be relevant to the mitogenic potential of ET-1 on VSMC. Our findings imply a role for ET-1 in the control of vascular function via both paracrine and autocrine regulatory mechanisms. The expression of prepro ET-1mRNA and peptide biosynthesis by rVSMC may have both short-term (e.g., vasoconstriction) and long-term (e.g., structural remodeling) consequences. A sustained loop of autocrine stimulation by ET-1 in SMC could contribute toward the pathogenesis of vasospasm and/or atherosclerosis.
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PMID:Stimulation of endothelin mRNA and secretion in rat vascular smooth muscle cells: a novel autocrine function. 207 71

Endothelial cells play an important regulatory role in the circulation as a physical barrier and as a source of a variety of regulatory substances. Endothelium-derived nitric oxide and prostacyclin are released in response to physical stimuli, hormones and platelet-derived substances and induce vascular relaxation and inhibition of platelet function. Certain substances can evoke a hyperpolarization of smooth muscle cells. In addition, endothelial cells can release several contracting factors (i.e. endothelin, thromboxane A2, angiotensin II, superoxide and unidentified endothelium-derived contracting factors), at least under certain conditions. Endothelial cells are also a source of growth inhibitors and promoters, such as heparin and heparin sulphates, platelet-derived growth factor and thrombospondin. Several vasoactive substances produced by the endothelium, such as nitric oxide, endothelin and angiotensin II may also play a role in the regulation of vascular growth. Thus, the endothelial layer can regulate vascular tone and growth. A dysfunction of these endothelium-dependent regulatory systems may play a role in cardiovascular diseases, such as hypertension and atherosclerosis.
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PMID:Endothelial control of vascular tone and growth. 220 57

An adhesive interaction between activated platelets and mononuclear phagocytes may contribute to the role these cells play in regulating inflammation, thrombosis, and atherosclerosis. We have previously shown that this adhesive interaction is mediated by the expression of the glycoprotein thrombospondin (TSP) on the surface of activated platelets. We now show that TSP-dependent platelet-monocyte interactions are mediated by glycoprotein IV (GPIV), an intrinsic membrane protein recently identified as a cell surface TSP receptor. Monoclonal antibodies to GPIV bound to cells of the human monocytoid line U937 as assessed by flow cytometry and inhibited the binding of 125I-TSP to the cell surface by 83%. U937 cells preincubated with anti-GPIV were not rosetted by thrombin-stimulated platelets (72% inhibition compared with control anti-monocyte antibodies). In addition, when platelets were stimulated in the presence of saturating concentrations of monoclonal antibodies to GPIV, only 18% of U937 cells were rosetted (78% inhibition). Control antibodies including anti-GPIb did not inhibit rosette formation. These data suggest that TSP can cross-link platelets and monocytes via an interaction with GPIV on the surface of both cells. This molecular bridge may mediate platelet-macrophage communication in various pathophysiologic settings.
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PMID:Glycoprotein IV mediates thrombospondin-dependent platelet-monocyte and platelet-U937 cell adhesion. 247 71

Marked atherosclerosis was produced in the coronary arteries (c.a.) of full-grown ("old") mini-pigs by combination of protracted hypercholesterolemia with two repetitions of irradiation of the heart region. "Sudden cardiac death" with occlusion of some peripheral c.a. occurred to 40% of the pigs within 15 to 21 weeks from the last irradiation. Growing ("young") pigs, after the same treatment, developed more marked atherosclerotic lesions in the c.a. than "old" pigs. There was a trend to a situation in which mortality (58%; p = 0.2) in "young" pigs was higher than in "old". When "old" pigs were treated with the calcium-channel blocker nifedipine (2 x 20 mg/day; mean body weight 66 kg), there was some trend to reduced mortality from 40% to 25% (p = 0.25). If the effects of age and nifedipine were combined, the difference in mortality (58% or 25%) was significant (p less than 0.05). In pigs that had died a "sudden cardiac death", the content of cholesteryl esters in the c.a. rose to values of greater than 60 x 10(-6) mol/g prot. In age-matched control pigs, the mean ester content was 2.8 or 1.2 x 10(-6) mol/g prot. in "young" and "old" pigs. In nonirradiated hypercholesterolemic pigs, the mean ester content in "young" animals was 39 x 10(-6) mol/g prot. but in "old" pigs it came to 4.8 x 10(-6) mol/g prot. 12 months after the "sudden cardiac death" period had ended, the ester content in the surviving pigs was 25 x 10(-6) mol/g prot. in "young" and 3.5 x 10(-6) mol/g prot. in "old" animals. Irradiation had produced some kind of healing effect. This regress in cholesteryl ester content was significantly and moderately delayed by nifedipine treatment. It did not otherwise change the cholesterol metabolism of the arteries. A probable explanation for the partly marked and rapid changes in cholesterol metabolism of c.a. was that there had been a change in phenotype of vascular smooth muscle cells, mainly localised to the intima of the c.a. The vascular endothelial cells influence the phenotype of vascular smooth muscle cells by stimulating proliferation and accumulation of cholesterol by growth factors (PDGF) which act via thrombospondin. By releasing heparin and/or heparin-like glycosaminoglycans, endothelium may inhibit the effect of thrombospondin on vascular smooth muscle cells. An additional contribution is possibly made by cholesterol from high-lipid macrophages.
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PMID:Relationship between coronary atherosclerosis and "sudden cardiac death". Effects of age and calcium blockers in hypercholesterolemic mini-pigs. 281 40

Although lipids have received most attention in relation to atherosclerosis, vessel injury also has a role in the development of atherosclerotic lesions. Thrombi that form at sites of injury can be incorporated into the wall, causing thickening, and platelets that adhere to damaged vessel walls release a growth factor (PDGF) that stimulates smooth muscle cell proliferation. The early lesions of atherosclerosis are focal and develop around vessel orifices and branches in relation to the patterns of blood flow and areas of increased permeability and endothelial cell damage. Platelets also contribute to the complications of advanced atherosclerosis caused by occlusive thrombi, thromboembolism, and spasm. The causes of vessel wall injury are not established, although there is evidence pointing to disturbed blood flow, hypertension, antigen--antibody complexes, complement, materials originating from platelets and white blood cells, bacteria, endotoxin, viruses, smoking, dietary lipids, homocystinemia, diabetes, other metabolic disorders, and stress. Platelets do not adhere to intact endothelium, but they adhere to the constituents of the subendothelium, release the contents of their granules (including PDGF), and form thromboxanes. If blood flow is disturbed, platelet--fibrin thrombi can form at sites of injury. Platelet adherence to a damaged wall does not require von Willebrand factor except under conditions of high wall shear. Repeated injury of a vessel wall leads to the development of lipid-rich atherosclerotic lesions, even in normocholesterolemic animals, but these lesions do not form if the experimental animals are made thrombocytopenic before injury is induced. Measurable changes in platelets that are associated with the clinical complications of atherosclerosis include shortened survival, release of granule contents (platelet factor 4, beta-thromboglobulin, thrombospondin), formation of thromboxanes, and decreased buoyant density. "Antiplatelet drugs" such as aspirin are proving to be beneficial in selected groups of patients, such as those with unstable angina. Thromboxane synthetase inhibitors and agents that block the thromboxane receptor on platelets are under investigation. Long term administration of "antiplatelet drugs" to affect the rate of development of atherosclerosis seems neither feasible nor desirable. Modification of dietary and smoking habits and control of hypertension are more likely to be beneficial for most individuals.
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PMID:The role of platelets in the development and complications of atherosclerosis. 351 36

Affinity-purified antisera against thrombospondin were used to locate the presence of this glycoprotein in frozen sections of several human tissues by immunofluorescence techniques. Immunostaining was observed in the peritubular connective tissue and in basement membrane regions beneath glandular epithelium in skin and lung. Intense immunostaining was observed at the dermal-epidermal junction in skin and in small blood vessels throughout this tissue. Skeletal muscle exhibited positive staining with anti-thrombospondin antisera within interstitial areas. Immunostaining was confined to the luminal portions of large blood vessels such as aorta. In large blood vessels that contained lesions of atherosclerosis, immunostaining was observed throughout the lesion area and was especially prominent surrounding some of the lesion cells. These results indicate that thrombospondin is located within the matrix of a variety of human tissues and supports the suggestion that this glycoprotein is an endogenous component of some extracellular matrices.
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PMID:Light microscopic immunolocation of thrombospondin in human tissues. 388 4

Accumulating evidence strongly implicates oxidized LDL (Ox-LDL) in the pathogenesis of atherosclerosis. Several receptors have been identified that bind and internalize Ox-LDL, but their relative importance in vivo is unclear. CD36 is an 88-kD transmembrane glycoprotein expressed on monocytes/macrophages, platelets, and microvascular endothelium that has been implicated as a putative receptor for Ox-LDL. We demonstrate that an anti-CD36 monoclonal antibody inhibited 50% of the specific binding and 26% of the specific degradation of Ox-LDL by human monocyte-derived macrophages. To characterize more completely this binding we evaluated interactions between CD36 and Ox-LDL in murine NIH-3T3 cells stably transfected with human CD36 cDNA. Ox-LDL bound to CD36-transfected 3T3 cells in a saturable manner. Specific binding, internalization, and degradation of Ox-LDL were increased fourfold in CD36-transfected cell lines compared with 3T3 cells transfected with vector alone. Binding of Ox-LDL to CD36-transfected 3T3 cells was inhibited by a panel of anti-CD36 antibodies and by soluble CD36 but not by thrombospondin. Specificity of binding was demonstrated by the equivalent binding of LDL and acetylated LDL to control and CD36-transfected 3T3 cells. The epitope or epitopes on Ox-LDL recognized by CD36 are undefined. Two observations suggest that CD36 recognizes a lipid moiety or that the lipid portion of the lipoprotein is essential for apoprotein recognition. The first is that the increased binding of Ox-LDL to CD36-transfected 3T3 cells is abrogated by delipidation of the lipoprotein, and the second is that oleic acid competes for the binding of Ox-LDL to CD36-transfected 3T3 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Oxidized LDL binds to CD36 on human monocyte-derived macrophages and transfected cell lines. Evidence implicating the lipid moiety of the lipoprotein as the binding site. 753 25

CD36, a multifunctional adhesion receptor e.g. for thrombospondin and collagen, as well as a scavenger receptor for oxidized low density lipoprotein, is expressed e.g. on platelets and monocytes. By this dual role it might be involved in early steps of atherosclerosis like the recruitment of monocytes and formation of foam cells. We therefore studied the effects of n-3 fatty acids on CD36 expression in human monocytic cells. Incorporation of eicosapentaenoic acid (EPA, C20:5n-3) and docosahexaenoic acid (DHA, C22:6n-3) into cellular phospholipids resulted in a significant reduction of CD36 expression at the mRNA and protein level, whereas arachidonic acid (AA, C20: 4n-6) and linoleic acid (LA, C18:2n-6) tended to increase CD36 expression compared to the control. This specific down-regulation of CD36 by n-3 fatty acids in cells involved in the initiation and progression of atherogenesis and inflammation, represents a further mechanism that may contribute to the beneficial effects of n-3 polyunsaturated fatty acids (PUFA) in these disorders.
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PMID:N-3 but not N-6 fatty acids reduce the expression of the combined adhesion and scavenger receptor CD36 in human monocytic cells. 755

The accumulation of excessive cholesterol-rich lipoproteins within vascular cells, the proliferation of vascular cells, and fibrin deposition are hallmark features of atherosclerosis. Evidence accumulated over the past few years supports the hypothesis that one member of the LDL receptor family, the low density lipoprotein receptor-related protein (LRP), affects the dynamics of each of these processes. LRP is expressed in several vascular cell types, including smooth muscle cells, and in macrophages, and is also expressed in these cells in atherosclerotic lesions. This receptor is a large endocytotic receptor that mediates the catabolism of a number of molecules known to be important in vascular biology, including apolipoprotein E- and lipoprotein lipase-enriched lipoproteins, thrombospondin, and plasminogen activators. The capacity of LRP to mediate lipoprotein catabolism may be a factor in the development of the lesion by contributing to the formation of foam cells. LRP has recently been shown to mediate the catabolism of thrombospondin, a molecule that has potent biological effects on cells of the vasculature. The regulation of its extracellular accumulation by LRP might modulate the dynamic processes of tissue remodeling associated with the response to vascular injury. In addition, LRP regulates the expression of plasmin activity by directly binding and mediating the cellular internalization of urokinase- and tissue-type plasminogen activators. The cellular removal of these two enzymes decreases the local profibrinolytic potential, possibly leading to a thrombotic state at lesion sites.
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PMID:LDL receptor-related protein: a multiligand receptor for lipoprotein and proteinase catabolism. 761 59


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