Abstract 3714: Heme Oxygenase 1 Determines the Outcome of Vulnerable Plaque
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.