Abstract
Plaque vulnerability is an important determinant in the prognosis of CAD. However the mechanism of transition from stable to vulnerable plaque (VP) remains unclear. Heme oxygenase 1 (HO-1) and its metabolites of heme degradation have been implicated in the cytoprotective defense response against oxidative injury. Here, we sought to assess the role of HO-1 in the development of VP in carotid artery disease in human and in a mouse model of VP. Atherectomy biopsies of 109 patients with clinical significant CAD were collected and stratified according to plaque morphology. HO-1 protein expression was determined by ELISA and was correlated with plaque parameters and pro-inflammatory biomarkers.To evaluate the function of HO-1 in VP, HO-1 was induced by CoPPIX injections in a murine model for VP in APOE −/− mice. HO-1 expression correlated closely to characteristics of atheromatous plaque vulnerability (p< 0.005) as indicated by intimal macrophage and lipid accumulation, and inverse correlations coincided with VSMCs and collagen. HO-1 expression levels correlated with proinflammatory biomarker titers including intraplaque MMP9 and IL-8 and IL6. HO-1 was mainly expressed in atheromatous infiltrating macrophages. In line with these observations, HO-1 expression was significantly increased in the VP vs. the stable lesions in our murine VP model. Systemic CoPPIX injections in the murine model resulted in an effective five-fold increase at HO-1 protein level. HO-1 induction did not affect the intima/media ratio, nor the percentage of intimal collagen or macrophages in the intima. However, systemic HO-1 induction significantly increased the percentage of intraplaque VSMCs by two-fold, while decreasing the percentage of lipids by two-fold. HO-1 protein expression closely correlated with histomorphological atherosclerotic plaque vulnerability and with expression levels of MMPs and pro-inflammatory cytokines in CAD patients. HO-1 induction in the murine VP model stabilized plaque morphology by reducing lipid accumulation and increasing VSMCs contect in these lesions. These data indicate that HO-1 expression in VP vs. stable plaques is enhanced as a compensatory atheroprotective response.
Published Version
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