Cholesterol modulates vascular reactivity to endothelin-1 by stimulating a pro-inflammatory pathway.
Hypercholesterolemia (HC) is associated with coronary endothelial dysfunction and increased circulating levels of endothelin-1. We show that pre-treatment of intact rat aortic rings with cholesterol synergistically enhances the vasoconstriction induced by endothelin-1 suggesting that elevated levels of cholesterol may predispose to hypertension by modulating the vascular reactivity to endogenous vasoconstrictors. Moreover, we report that SB202190, a selective inhibitor of p38 MAPK, and PD98059 an inhibitor of MEK1/2 are able to abolish the vasoactive properties of cholesterol. MK-886, an inhibitor of 5-lipoxygenase is inefficient at blocking the vasoactive properties of cholesterol whereas NS-398, a selective inhibitor of cyclooxygenase-2 (COX-2) completely abolishes cholesterol-induced vasoconstriction. In intact rat aortae, cholesterol stimulates prostaglandin E(2) and prostaglandin F(2 alpha) production, an effect that can be completely prevented by inhibiting p38 MAPK, or COX-2. In vitro, cholesterol appears to stimulate a similar pro-inflammatory pathway in human cerebrovascular smooth muscle cells. Disruption of the MAPK/COX-2 pathway may represent a valuable therapy to block the hypertension associated with HC, as well as the development of atherosclerosis.
Roskamp Institute, University of South Florida, 3515 E. Fletcher Avenue, Tampa, Florida, 33613, USA. dparis@coml.med.usf.edu
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Paris
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Town
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Humphrey
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Yokota
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Mullan
D000818:Animals; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation; D002784:Cholesterol / Q000378:metabolism* / Q000494:pharmacology; D051546:Cyclooxygenase 2; D015237:Dinoprost / Q000096:biosynthesis; D015232:Dinoprostone / Q000096:biosynthesis; D004357:Drug Synergism; D019332:Endothelin-1 / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D006937:Hypercholesterolemia / Q000378:metabolism*; D066298:In Vitro Techniques; D007249:Inflammation / Q000378:metabolism*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D016859:Lipoxygenase Inhibitors; D008297:Male; D008565:Membrane Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases
D019332:Endothelin-1; D007527:Isoenzymes; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D002784:Cholesterol; D015237:Dinoprost; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone