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      Die Bedeutung entzündlicher Reaktionen für die Pathogenese der Arteriosklerose

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          Abstract

          Während die zellulären Mechanismen der Pathogenese der Arteriosklerose intensiv untersucht worden sind, ist über die Mechanismen, die zu einer bevorzugten Lokalisation arteriosklerotischer Läsionen in bestimmten Gefäßarealen führen, weniger bekannt. Zur Untersuchung dieser Mechanismen wurden Endothelzellen aus menschlichen Koronararterien, einem Gefäßbereich, in dem häufig arteriosklerotische Läsionen beobachtete werden, isoliert und kultiviert. Endothelzellen der Mikrozirkulation menschlicher Herzen wurden unter gleichen Bedingungen kultiviert und die Reaktionen beider Zellarten verglichen. Inkubation der Zellen mit den in Bezug auf die Bildung arteriosklerotischer Plaques besonders pathogenen oxidierten LDL induzierte in makrovaskulären koronaren Endothelzellen eine stärkere Zunahme der PAI-1 Aktivität (182%, p<0,05) als in mikrovaskuläre Zellen (144%, p < 0,05) während nicht oxidierte n-LDL die sezernierte PAI-1 Aktivität nicht beeinflußten. Nach Stimulation mit Angiotensin II (10-11 - 10-5 M) zeigte sich auf makrovaskulären koronaren Endothelzellen eine stärkere Expression des Adhäsionsmoleküls E-Selectin als auf mikrovaskulären Endothelzellen. Die Angiotensin II induzierte E-Selectin Expression führte in vitro auch funktionell zu einer erhöhten Adhäsion von HL60 Zellen unter Flußbedingungen. Dagegen wurde die für die Leukozytenrekrutierung im Rahmen inflammatorischer Reaktionenen wichtige L-Selectin abhängige Adhäsion von Angiotensin II nicht induziert. Stimualtion mit TNF( führte überwiegend an mikrovaskulären Endothelzellen zum Auftreten einer L-Selectin abhängigen Adhäsion. Die unterschiedliche Reaktion mikro- und makrovaskulärer kardialer Endothelzellen bietet eine Möglichkeit, zellspezifische Differenzierung und preferentielle Lokalisation arterioklerotischer Läsionen in makrovaskulären Gefäßbereichen einerseits und das Auftreten entzündlicher Reaktionen im Bereich der Mikrozirkulation andererseits zu erklären.

          Abstract

          While the cellular mechanisms of atherosclerosis have been intensively studied, the mechanisms leading to preferential localization of atherosclerotic lesions are less well understood. To further define these mechanisms, endothelial cells from coronary arteries, i.e. vessels with frequent atherosclerotic lesions, were isolated and grown in vitro. In order to compare the reactions of both cell types, endothelial cells derived from microvessels of human hearts were isolated and cultured under identical conditions. Incubation of endothelial cells with oxidized LDL (75 µg/ml protein) induced a significant increase in PAI-1 activity (182 %, p<0.05) in coronary macrovascular endothelial cells. This stimulatory effect of ox-LDL was less significant in microvascular endothelial cells (144%, p<0,05). n-LDL did not influence secreted PAI-1 activity. Stimulation with angiotensin II induced expression of E-selectin more effectively in coronary macrovascular than in microvascular endothelial cells. In addition, angiotensin II-induced E-selectin expression led to increased E-selectin-dependent adhesion of HL60 cells to coronary macrovascular endothelial cells under flow conditions, while only little effects were observed with cardiac microvascular endothelial cells. In contrast, L-selectin-dependent adhesion, which has been shown to play an important role in inflammatory reactions, was preferentially observed in cardiac microvascular endothelial cells and could only be stimulated with TNF(, not by angiotensin II. Therefore, these cellular differences may in part explain specific properties of cardiac endothelial cells: Such that atherosclerotic lesions are localized in macrovascular vessel segments, whereas inflammatory responses are predominantly found in the microvasculature.

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            The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum.

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              Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease.

              Observational studies suggest that people who consume more fruits and vegetables containing beta carotene have somewhat lower risks of cancer and cardiovascular disease, and earlier basic research suggested plausible mechanisms. Because large randomized trials of long duration were necessary to test this hypothesis directly, we conducted a trial of beta carotene supplementation. In a randomized, double-blind, placebo-controlled trial of beta carotene (50 mg on alternate days), we enrolled 22,071 male physicians, 40 to 84 years of age, in the United States; 11 percent were current smokers and 39 percent were former smokers at the beginning of the study in 1982. By December 31, 1995, the scheduled end of the study, fewer than 1 percent had been lost to follow-up, and compliance was 78 percent in the group that received beta carotene. Among 11,036 physicians randomly assigned to receive beta carotene and 11,035 assigned to receive placebo, there were virtually no early or late differences in the overall incidence of malignant neoplasms or cardiovascular disease, or in overall mortality. In the beta carotene group, 1273 men had any malignant neoplasm (except nonmelanoma skin cancer), as compared with 1293 in the placebo group (relative risk, 0.98; 95 percent confidence interval, 0.91 to 1.06). There were also no significant differences in the number of cases of lung cancer (82 in the beta carotene group vs. 88 in the placebo group); the number of deaths from cancer (386 vs. 380), deaths from any cause (979 vs. 968), or deaths from cardiovascular disease (338 vs. 313); the number of men with myocardial infarction (468 vs. 489); the number with stroke (367 vs. 382); or the number with any one of the previous three end points (967 vs. 972). Among current and former smokers, there were also no significant early or late differences in any of these end points. In this trial among healthy men, 12 years of supplementation with beta carotene produced neither benefit nor harm in terms of the incidence of malignant neoplasms, cardiovascular disease, or death from all causes.
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                Author and article information

                Journal
                Medizinische Fakultät - Universitätsklinikum Charité, Humboldt-Universität (kvv )
                17 July 2001
                1 August 2002
                Affiliations
                [1 ] Medizinische Fakultät
                [2 ] Frankfurt/Main
                [3 ] Göttingen
                Article
                oai:HUBerlin.de:20061
                07eb9226-c651-4876-94cb-4a436fce8a96
                History

                Medizin,Endothelzellen,E-Selectin,L-Selectin,oxidierte LDL,endothelial cells,oxidized LDL,YC1100

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