Caveolin-1 influences vascular protease activity and is a potential stabilizing factor in human atherosclerotic disease.
Caveolin-1 (Cav-1) is a regulatory protein of the arterial wall, but its role in human atherosclerosis remains unknown. We have studied the relationships between Cav-1 abundance, atherosclerotic plaque characteristics and clinical manisfestations of atherosclerotic disease.We determined Cav-1 expression by western blotting in atherosclerotic plaques harvested from 378 subjects that underwent carotid endarterectomy. Cav-1 levels were significantly lower in carotid plaques than non-atherosclerotic vascular specimens. Low Cav-1 expression was associated with features of plaque instability such as large lipid core, thrombus formation, macrophage infiltration, high IL-6, IL-8 levels and elevated MMP-9 activity. Clinically, a down-regulation of Cav-1 was observed in plaques obtained from men, patients with a history of myocardial infarction and restenotic lesions. Cav-1 levels above the median were associated with absence of new vascular events within 30 days after surgery [0% vs. 4%] and a trend towards lower incidence of new cardiovascular events during longer follow-up. Consistent with these clinical data, Cav-1 null mice revealed elevated intimal hyperplasia response following arterial injury that was significantly attenuated after MMP inhibition. Recombinant peptides mimicking Cav-1 scaffolding domain (Cavtratin) reduced gelatinase activity in cultured porcine arteries and impaired MMP-9 activity and COX-2 in LPS-challenged macrophages. Administration of Cavtratin strongly impaired flow-induced expansive remodeling in mice. This is the first study that identifies Cav-1 as a novel potential stabilizing factor in human atherosclerosis. Our findings support the hypothesis that local down-regulation of Cav-1 in atherosclerotic lesions contributes to plaque formation and/or instability accelerating the occurrence of adverse clinical outcomes. Therefore, given the large number of patients studied, we believe that Cav-1 may be considered as a novel target in the prevention of human atherosclerotic disease and the loss of Cav-1 may be a novel biomarker of vulnerable plaque with prognostic value.
Rodriguez-Feo
Juan A
JA
Department of Cardiology, Experimental Cardiology Laboratory, University Medical Center, Utrecht, The Netherlands.
Hellings
Willem E
WE
Moll
Frans L
FL
De Vries
Jean-Paul P M
JP
van Middelaar
Ben J
BJ
Algra
Ale
A
Sluijter
Joost
J
Velema
Evelyn
E
van den Broek
Theo
T
Sessa
William C
WC
De Kleijn
Dominique P V
DP
Pasterkamp
Gerard
G
D000368:Aged; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism*; D002340:Carotid Artery Diseases / Q000378:metabolism; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D016209:Interleukin-8 / Q000276:immunology / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice
D051242:Caveolin 1; D015850:Interleukin-6; D016209:Interleukin-8; D020780:Matrix Metalloproteinase 9