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(Circulation. 2009;119:3017-3027.)
© 2009 American Heart Association, Inc.

Vascular Medicine

Heme Oxygenase 1 Determines Atherosclerotic Lesion Progression Into a Vulnerable Plaque

Caroline Cheng, PhD^*; Annemarie M. Noordeloos, MSc^*; Viktoria Jeney, MSc; Miguel P. Soares, PhD; Frans Moll, PhD, MD; Gerard Pasterkamp, PhD, MD; Patrick W. Serruys, PhD, MD; Henricus J. Duckers, PhD, MD

From the Molecular Cardiology Laboratory, Experimental Cardiology, Thoraxcenter, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands (C.C., A.M.N., P.W.S., H.J.D.); Departments of Vascular Surgery (F.M.) and Cardiology (G.P.), University Medical Center Utrecht, Utrecht, the Netherlands; and Inflammation Laboratory, Instituto Gulbenkian de Ciencia, Oeiras, Portugal (V.J., M.P.S.).

Correspondence to H.J. Duckers, MD, PhD, FESC, Molecular Cardiology Laboratory, Ee2389A, Thoraxcenter, Erasmus University Medical Center, s'Gravendijksewal 230, 3015 CE Rotterdam, the Netherlands. E-mail h.duckers{at}erasmusmc.nl

Received July 22, 2008; accepted April 14, 2009.

Background— The molecular regulation for the transition from stable to vulnerable plaque remains to be elucidated. Heme oxygenase 1 (HO-1) and its metabolites have been implicated in the cytoprotective defense against oxidative injury in atherogenesis. In this study, we sought to assess the role of HO-1 in the progression toward plaque instability in carotid artery disease in patients and in a murine model of vulnerable plaque development.

Methods and Results— Atherectomy biopsy from 112 patients with clinical carotid artery disease was collected and stratified according to characteristics of plaque vulnerability. HO-1 expression correlated closely with features of vulnerable human atheromatous plaque (P<0.005), including macrophage and lipid accumulation, and was inversely correlated with intraplaque vascular smooth muscle cells and collagen deposition. HO-1 expression levels correlated with the plaque destabilizing factors matrix metalloproteinase-9, interleukin-8, and interleukin-6. Likewise, in a vulnerable plaque model using apolipoprotein E^–/– mice, HO-1 expression was upregulated in vulnerable versus stable lesions. HO-1 induction by cobalt protoporphyrin impeded lesion progression into vulnerable plaques, indicated by a reduction in necrotic core size and intraplaque lipid accumulation, whereas cap thickness and vascular smooth muscle cells were increased. In contrast, inhibition of HO-1 by zinc protoporphyrin augmented plaque vulnerability. Plaque stabilizing was prominent after adenoviral transduction of HO-1 compared with sham virus–treated animals, providing proof that the observed effects on plaque vulnerability were HO-1 specific.

Conclusions— Here we demonstrate in a well-defined patient group and a murine vulnerable plaque model that HO-1 induction reverses plaque progression from a vulnerable plaque to a more stable phenotype as part of a compensatory atheroprotective response.

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CLINICAL PERSPECTIVE

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