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Journal ArticleDOI

The pathogenesis of atherosclerosis: a perspective for the 1990s

29 Apr 1993-Nature (Nature Publishing Group)-Vol. 362, Iss: 6423, pp 801-809
TL;DR: The ability to control the expression of genes encoding these molecules and to target specific cell types provides opportunities to develop new diagnostic and therapeutic agents to induce the regression of the lesions and, possibly, to prevent their formation.
Abstract: Atherosclerosis, the principal cause of heart attack, stroke and gangrene of the extremities, is responsible for 50% of all mortality in the USA, Europe and Japan. The lesions result from an excessive, inflammatory-fibroproliferative response to various forms of insult to the endothelium and smooth muscle of the artery wall. A large number of growth factors, cytokines and vasoregulatory molecules participate in this process. Our ability to control the expression of genes encoding these molecules and to target specific cell types provides opportunities to develop new diagnostic and therapeutic agents to induce the regression of the lesions and, possibly, to prevent their formation.
Citations
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Journal ArticleDOI
TL;DR: Atherosclerosis is an inflammatory disease as discussed by the authors, and it is a major cause of death in the United States, Europe, and much of Asia, despite changes in lifestyle and use of new pharmacologic approaches to lower plasma cholesterol concentrations.
Abstract: Atherosclerosis is an inflammatory disease. Because high plasma concentrations of cholesterol, in particular those of low-density lipoprotein (LDL) cholesterol, are one of the principal risk factors for atherosclerosis,1 the process of atherogenesis has been considered by many to consist largely of the accumulation of lipids within the artery wall; however, it is much more than that. Despite changes in lifestyle and the use of new pharmacologic approaches to lower plasma cholesterol concentrations,2,3 cardiovascular disease continues to be the principal cause of death in the United States, Europe, and much of Asia.4,5 In fact, the lesions of atherosclerosis represent . . .

19,881 citations

Journal Article
TL;DR: Despite changes in lifestyle and the use of new pharmacologic approaches to lower plasma cholesterol concentrations, cardiovascular disease continues to be the principal cause of death in the United States, Europe, and much of Asia.

9,749 citations

Journal ArticleDOI
13 Dec 2001-Nature
TL;DR: This integrating paradigm provides a new conceptual framework for future research and drug discovery in diabetes-specific microvascular disease and seems to reflect a single hyperglycaemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain.
Abstract: Diabetes-specific microvascular disease is a leading cause of blindness, renal failure and nerve damage, and diabetes-accelerated atherosclerosis leads to increased risk of myocardial infarction, stroke and limb amputation. Four main molecular mechanisms have been implicated in glucose-mediated vascular damage. All seem to reflect a single hyperglycaemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain. This integrating paradigm provides a new conceptual framework for future research and drug discovery.

8,289 citations

Journal ArticleDOI

6,184 citations

Journal ArticleDOI
TL;DR: The reduction associated with the use of aspirin in the risk of a first myocardial infarction appears to be directly related to the level of C-reactive protein, raising the possibility that antiinflammatory agents may have clinical benefits in preventing cardiovascular disease.
Abstract: Background Inflammation may be important in the pathogenesis of atherothrombosis. We studied whether inflammation increases the risk of a first thrombotic event and whether treatment with aspirin decreases the risk. Methods We measured plasma C-reactive protein, a marker for systemic inflammation, in 543 apparently healthy men participating in the Physicians' Health Study in whom myocardial infarction, stroke, or venous thrombosis subsequently developed, and in 543 study participants who did not report vascular disease during a follow-up period exceeding eight years. Subjects were randomly assigned to receive aspirin or placebo at the beginning of the trial. Results Base-line plasma C-reactive protein concentrations were higher among men who went on to have myocardial infarction (1.51 vs. 1.13 mg per liter, P<0.001) or ischemic stroke (1.38 vs. 1.13 mg per liter, P = 0.02), but not venous thrombosis (1.26 vs. 1.13 mg per liter, P = 0.34), than among men without vascular events. The men in the quartile wit...

5,489 citations

References
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Journal ArticleDOI
31 Mar 1988-Nature
TL;DR: Cloning and sequencing of preproendothelin complementary DNA shows that mature endothelin is generated through an unusual proteolytic processing, and regional homologies to a group of neurotoxins suggest that endothelins is an endogenous modulator of voltage-dependent ion channels.
Abstract: An endothelium-derived 21-residue vasoconstrictor peptide, endothelin, has been isolated, and shown to be one of the most potent vasoconstrictors known. Cloning and sequencing of preproendothelin complementary DNA shows that mature endothelin is generated through an unusual proteolytic processing, and regional homologies to a group of neurotoxins suggest that endothelin is an endogenous modulator of voltage-dependent ion channels. Expression of the endothelin gene is regulated by several vasoactive agents, indicating the existence of a novel cardiovascular control system.

10,651 citations

Journal ArticleDOI
02 Aug 1990-Nature
TL;DR: Three families of cell-surface molecules regulate the migration of lymphocytes and the interactions of activated cells during immune responses.
Abstract: The adhesive interactions of cells with other cells and with the extracellular matrix are crucial to all developmental processes, but have a central role in the functions of the immune system throughout life Three families of cell-surface molecules regulate the migration of lymphocytes and the interactions of activated cells during immune responses

6,595 citations

Journal ArticleDOI
TL;DR: A response-to-injury hypothesis of atherogenesis proposes that "injury" to the endothelium is the initiating event in atherosclerosis, and intimal smooth-muscle proliferation as the key event in the development of the advanced lesions of Atherosclerosis.
Abstract: CARDIOVASCULAR disease remains the chief cause of death in the United States and Western Europe, and atherosclerosis, the principal cause of myocardial and cerebral infarction, accounts for the majority of these deaths.1 This review, like its predecessor,2 will not attempt to cover all literature on atherosclerosis. In a previous review of the pathogenesis of atherosclerosis,2 Glomset and I discussed various hypotheses of atherogenesis2 3 4 5 6 7 and emphasized the importance of intimal smooth-muscle proliferation as the key event in the development of the advanced lesions of atherosclerosis. The response-to-injury hypothesis of atherogenesis2 3 4 5 6 proposes that "injury" to the endothelium is the initiating event in . . .

4,835 citations

Journal ArticleDOI
TL;DR: The two hypotheses to explain the pathogenesis of atherosclerosis, the "incrustation" hypothesis and the "lipid" hypothesis, are now known.
Abstract: IN the 19th century there were two major hypotheses to explain the pathogenesis of atherosclerosis: the "incrustation" hypothesis and the "lipid" hypothesis. The incrustation hypothesis of von Rokitansky,1 proposed in 1852 and modified by Duguid,2 suggested that intimal thickening resulted from fibrin deposition, with subsequent organization by fibroblasts and secondary lipid accumulation. The lipid hypothesis, proposed by Virchow3 in 1856, suggested that lipid in the arterial wall represented a transduction of blood lipid, which subsequently formed complexes with acid mucopolysaccharides; lipid accumulated in arterial walls because mechanisms of lipid deposition predominated over those of removal. The two hypotheses are now . . .

3,779 citations