Abstract
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.
Highlights
Atherosclerotic plaque formation, destabilization and rupture with subsequent thrombus formation give rise to acute coronary syndromes [1], symptomatic carotid artery disease [2] and sudden cardiac death [3]
Cav-1 antibody was able to detect two bands with a relative molecular weight of 24KD and 22 KD demonstrating the presence of the two known isoforms of Cav-1; (Figure 1A) Cav-1 protein expression levels were strongly reduced in atherosclerotic plaques compared with non-atherosclerotic mammary arteries (Figure 1B)
To study if Cav-1 via its scaffolding domain (CSD) is involved in matrix metalloprotease (MMP) regulation and the expression of pro-inflammatory mediators, we evaluated the effect of cell-permeable synthetic peptides derived from the human Cav-1 scaffolding domain (CSD) known as Cavtratin on gelatinolytic activity and cycloxygenase-2 (COX-2) expression in cultured murine Raw-264.7 macrophages
Summary
Atherosclerotic plaque formation, destabilization and rupture with subsequent thrombus formation give rise to acute coronary syndromes [1], symptomatic carotid artery disease [2] and sudden cardiac death [3]. The main goal of this study is to identify the expression patterns of specific proteins expressed within the vascular tree that may make patients prone to suffer cardiovascular events in all vascular territories These proteins, diffusely expressed in the vasculature, could be locally detected using local molecular imaging or in endarterectomy specimens, and serve as a surrogate marker to identify the patient at risk for future adverse cardiovascular events, the so-called vulnerable patient [9]. In this context, we have tested the possibility that Caveolin-1 (Cav1) plaque abundance is related to plaque and patient stability
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
