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)

Angiotensin II is a potent vasoconstrictor that has been also implicated in vascular hyperproliferative diseases, including atherosclerosis and restenosis following angioplasty. Treatment of cultured, serum-starved rat aortic smooth muscle cells with angiotensin II causes rapid protein tyrosine phosphorylation that precedes cell mitogenesis. We have identified two of the phosphoproteins as paxillin (75 kilodaltons) and the tyrosine kinase pp125Fak, both components of actin-associated focal adhesion sites. Angiotensin II stimulated a 5-fold increase in the tyrosine phosphorylation of paxillin and a smaller (1.5-fold) increase in pp125Fak tyrosine phosphorylation. Paxillin tyrosine phosphorylation was evident within 1 minute, and was maximal after 10 minutes. Similar elevated protein tyrosine phosphorylation levels of paxillin were obtained with exposure of the rat aortic smooth muscle cells to peptides endothelin-1 and alpha-thrombin that function, as angiotensin II, through binding to members of the seven transmembrane domain G protein coupled receptors. Angiotensin II treatment also stimulated the production of a well-ordered actin-containing stress fiber network and prominent paxillin-containing focal adhesions. The focal adhesions stained intensely with anti-phosphotyrosine antibody suggesting the tyrosine phosphorylation of paxillin and cytoskeletal reorganization were tightly coupled. Angiotensin II receptor occupancy has been shown previously to lead to protein kinase C activation. However, compared to angiotensin II stimulation, a smaller, delayed increase in paxillin tyrosine phosphorylation was observed following direct protein kinase C activation by the phorbol ester phorbol 12-myristate-13-acetate. Paxillin tyrosine phosphorylation was selective for certain agonists since no increase in tyrosine phosphorylation of this protein was observed following exposure to the potent mitogen PDGF. Thus, actin-based cytoskeletal changes involving sites of cell adhesion to the extracellular matrix may play an important role in normal and pathophysiologic smooth muscle cell growth regulation in response to certain angiotensin II-type vasoactive agonists.
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PMID:Angiotensin II stimulation of rapid paxillin tyrosine phosphorylation correlates with the formation of focal adhesions in rat aortic smooth muscle cells. 753 46

Hypertension is a complex disease, the treatment of which should not only lower systolic and diastolic blood pressure but also attenuate the secondary consequences of the disease. These include vascular injury (including atherosclerosis), stroke, left ventricular hypertrophy, and renal damage. To establish whether the long-acting, vascular-selective calcium antagonist amlodipine attenuates some of these secondary consequences of hypertension, 5-week-old stroke-prone hypertensive and 8-week-old spontaneously hypertensive rats were treated (orally) with 5 mg/kg/day and 10 mg/kg/day amlodipine, respectively, for 30 weeks. The treatment resulted in a significant lowering of systolic blood pressure, accompanied by reduced cardiac hypertrophy and prolonged survival. Evidence for a protective effect of amlodipine on the vasculature was obtained by treating cholesterol-fed rabbits with 1-5 mg/kg/body weight/day. This resulted in a reduction in vascular Ca2+ overloading and a reduced incidence of sudanophilic lesion formation. Protection against ischemia-induced changes in the myocardium included a reduction in the ischemia-induced externalization of endothelin-1 binding sites.
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PMID:End-organ involvement and calcium antagonist therapy: animal studies. 760 72

This review discusses recent experimental findings in prostacyclin, nitric oxide and endothelin research. Prostacyclin formation by endothelial cells in atherosclerosis and diabetes is reviewed and the synthesis of prostacyclin by cyclooxygenase 1 and 2 (COX-1 and COX-2) is discussed. Further work on nitric oxide describes its involvement in septic and haemorrhagic shock and its interactions with the cyclooxygenase pathway. Recent studies in endothelin research include the development of both selective and orally active receptor antagonists, characterization of endothelin converting enzymes and the involvement of endothelin-1 in inflammation and wound repair.
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PMID:Regulatory mechanisms of the vascular endothelium: an update. 762 May 13

Recent studies suggest that endothelin and its receptors may be involved in atherogenesis. To test this hypothesis, cholesterol-fed hamsters were treated with a selective endothelin subtype A (ETA) receptor antagonist BMS-182874. Characterization of hamster atherosclerotic plaques indicated that they contained a fibrous cap of smooth muscle cells, large macrophage-foam cells, and epitopes of oxidized low density lipoprotein. Messenger RNA for both ETA and ETB receptors was detected in aortic endothelial cells, in medial smooth muscle cells, and in macrophage-foam cells and smooth muscle cells of the fibro-fatty plaques. BMS-182874 inhibited the endothelin-1-induced pressor response whereas the depressor effect was unaltered, suggesting that vascular ETA receptors were selectively blocked in vivo. In hyperlipidemic hamsters, BMS-182874 decreased the area of the fatty streak by reducing the number and size of macrophage-foam cells. The results indicated that ETA receptors and thus endothelin promoted the early inflammatory phase of atherosclerosis.
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PMID:Selective blockade of the endothelin subtype A receptor decreases early atherosclerosis in hamsters fed cholesterol. 771 49

Acute and chronic rejection are frequent and significant complications of cardiac transplantation, and graft arteriosclerosis is the leading cause of death beyond the first year after transplant. Levels of endothelin-1 (ET-1) are elevated in plasma of patients with cardiac allografts and those with symptomatic vascular atherosclerosis, but little is known about the role of ET-1 in these processes. This study examined intragraft ET-1 expression in rat cardiac models of acute rejection and chronic rejection associated with graft arteriosclerosis. Corrected ET-1 gene transcript levels were measured with a [32P]dCTP reverse transcription polymerase chain reaction assay normalized with glyceraldehyde-3-phosphate dehydrogenase, and the gene product was evaluated by immunohistology with a monospecific anti-ET-1 antibody at different time points after transplant. ET-1 mRNA levels were significantly increased in acutely rejected (Wistar-Furth rat cardiac allografts transplanted into Lewis rat recipients) and chronically rejected (Lewis allografts transplanted into F344 recipients) vascularized cardiac allografts as compared with isograft controls. In acutely rejected allografts, peak expression occurred on day 5 after transplant. In chronically rejected allografts, the increase in ET-1 mRNA was sustained on days 7, 28, and 75. In both acutely and chronically rejected allografts, ET-1 mRNA upregulation was not seen in host spleens or paired host hearts. Immunohistological analysis confirmed that the bulk of ET-1 peptide expression was localized to mononuclear cells that diffusely infiltrated the graft interstitium (acute rejection and early chronic rejection) and accumulated within the neointima of chronically rejecting hearts with arteriosclerosis. These observations, taken together with in vitro data showing that ET-1 production is stimulated by certain cytokines, indicate that the allogeneic stimulus within rejecting vascularized cardiac allografts, presumably cytokine mediated, leads to significant intragraft up-regulation of ET-1 mRNA and peptide expression. The local up-regulation of this vasoactive and mitogenic peptide within acutely and chronically rejected cardiac allografts suggests that ET-1 may be involved in the development of graft arteriosclerosis.
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PMID:Up-regulation of endothelin-1 mRNA and peptide expression in rat cardiac allografts with rejection and arteriosclerosis. 774 1

Although the inferior epigastric artery has been used as an alternative arterial graft for coronary artery bypass grafting, little is known about the contractile and relaxation characteristics of this artery. This study was designed to compare the pharmacologic reactivity of the two arterial conduits--the inferior epigastric artery and the internal mammary artery. Forty-one inferior epigastric artery ring segments from eight patients undergoing coronary grafting and 62 internal mammary artery ring segments were set up in organ baths under physiologic pressure. The contractility was determined from the contraction induced by the depolarizing agent potassium and receptor-mediated vasoconstrictor agents, norepinephrine, U46619, and endothelin-1. Endothelium-dependent relaxation was induced by the calcium ionophore A23187, a non-receptor agonist for endothelium-derived relaxing factor, and acetylcholine, a receptor agonist for endothelium-derived relaxing factor. Glyceryl trinitrate was used to study endothelium-independent relaxation. The maximal response (either contraction or relaxation) and the effective concentration causing 50% of the maximal response for these two arteries were compared. There was no difference (p > 0.05) either in the maximal contraction force (5.30 +/- 0.87 versus 4.76 +/- 0.89 gm for potassium, 5.13 +/- 0.67 versus 4.47 +/- 1.15 gm for norepinephrine, 8.04 +/- 1.23 versus 6.23 +/- 0.99 gm for U46619, and 4.88 +/- 0.69 versus 5.57 +/- 0.93 for endothelin-1 (n = 6 to 10 for each vasoconstrictor) or in the maximal relaxation induced by glyceryl trinitrate (86.46% versus 92.98%, n = 6) or by acetylcholine (20.72% versus 45.51%, n = 5) between the inferior epigastric artery and internal mammary artery. The effective concentration causing half maximal response to all vasoconstrictors and vasodilators was similar between the two arteries (p > 0.05). However, A23187 induced significantly less relaxation in the inferior epigastric artery (38.42 +/- 15.49%, n = 6) than in the internal mammary artery (71.89 +/- 7.17%, n = 9, p < 0.05). We conclude that contractility, endothelium-independent relaxation, and receptor-mediated endothelium-dependent relaxation are similar in the inferior epigastric artery and the internal mammary artery. However, the endothelium of this arterial graft has less ability to respond to the non-receptor-mediated endothelium-derived relaxing factor stimulant. The influence of this difference on the prevalence of atherosclerosis and long-term patency rate in the inferior epigastric artery remains to be studied.
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PMID:Functional comparison between the human inferior epigastric artery and internal mammary artery. Similarities and differences. 781 88

Through the release of a variety of relaxing and contracting factors, including nitric oxide and endothelin-1, the endothelium exerts a complex paracrine influence on vascular smooth muscle cells. Dysfunction of these mechanisms for regulating tone may have relevance to various clinical entities, including hypertension, atherosclerosis, renal failure, and diabetes.
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PMID:Endothelial regulation of vascular tone. 792 67

Platelets can interact with the blood vessel wall in numerous ways. By releasing vasoactive substances such as adenosine tri- and diphosphate as well as serotonin, platelets can stimulate the formation of nitric oxide and prostacyclin within endothelial cells. Under physiological conditions, this may provide an important protective mechanism providing platelet inhibition and increased local blood flow at sites of platelet activation. In addition, platelets also can stimulate the formation of the vasoconstrictor peptide endothelin-1 within endothelial cells. On the other hand, platelet-derived substances such as thromboxane and serotonin can activate vascular smooth muscle cells and cause profound vasoconstriction. Platelet-vessel wall interaction is normally very low due to protective mechanisms. In disease states, however, endothelial dysfunction increases platelet-vessel wall interaction. Low-density lipoproteins markedly reduced endothelium-dependent relaxations to aggregating platelets and serotonin. Even more marked changes in endothelial function occur in atherosclerosis. These functional alterations of platelet-vessel wall interaction may play an important role in the pathogenesis of cardiovascular disease.
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PMID:Platelet-vessel wall interaction: role of nitric oxide, prostaglandins and endothelins. 802 45

Hypercholesterolemia is an important contributor to the development of intimal hyperplasia and superimposed accelerated atherosclerosis in vein bypass grafts. This study examines the effect of dietary modification of serum cholesterol on the development of intimal hyperplasia and vasomotor function of vein grafts. Thirty male New Zealand White rabbits had a right carotid vein bypass graft and were put to death 28 days after the operation. Twenty animals received a 1% cholesterol diet for 4 weeks before the operation. In 10 animals this diet was continued until harvest (hypercholesterolemia group). In another 10 animals the diet was changed to standard rabbit chow on the day of the surgical procedure and continued until harvest (cholesterol reduction group). The last 10 animals were control subjects. Vein grafts were harvested either for histologic study or for in vitro isometric tension studies. Cumulative dose response curves to norepinephrine, serotonin, bradykinin, and endothelin-1 were determined. After in situ pressure fixation, intimal thicknesses of the vein grafts were measured by videomorphometry. The change in diet produced a 74% reduction in serum cholesterol concentration within 28 days. There was a 26% reduction in the intimal thickness of vein graft intimal hyperplasia and the macroscopic disappearance of atheromatous lesions from the graft wall, which are always observed in vein grafts from the hypercholesterolemia group. Cholesterol reduction did not change hypercholesterolemia-induced agonist supersensitivity. Therefore, cholesterol reduction slows the formation of intimal hyperplasia in vein grafts but does not prevent the persistence of the hypercholesterolemia-associated smooth muscle phenotype.
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PMID:Postoperative reduction of high serum cholesterol concentrations and experimental vein bypass grafts. Effect on the development of intimal hyperplasia and abnormal vasomotor function. 807 49

The effect of short-term nicotine consumption on endothelin-1 (ET-1) levels was studied in 10 male healthy smokers. Volunteers smoked in random order on 3 separate days a low-tar cigarette or a high-tar cigarette, or were studied without having smoked (no-cigarette experiment). ET-1, corticotropin, and cortisol levels, heart rate, and blood pressure were determined before and 1, 3, 5, 10, 20, and 30 minutes after smoking. In contrast to results obtained after smoking a low-tar cigarette or not smoking, smoking a high-tar cigarette resulted in a significant increase in ET-1 levels within 10 minutes, followed by an increase in corticotropin levels within 20 minutes after smoking. Thirty minutes after smoking, cortisol levels were higher after a high-tar cigarette compared with a low-tar cigarette or no smoking. Increases in heart rate and systolic blood pressure were likewise higher after smoking a high-tar cigarette than after smoking a low-tar cigarette. In conclusion, it is tempting to speculate that ET-1 may indeed act as the long-searched-for link between vasopressin and corticotropin-releasing hormone (CRH) and thus play an essential role in the stimulation of the hypothalamic-pituitary-adrenal axis. In addition, these results suggest that the increase in the level of ET-1, a powerful vasoconstrictor and mitogen, may play an important part in the disease mechanisms of atherosclerosis arising from smoking.
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PMID:Elevated endothelin-1 levels after cigarette smoking. 813 72


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