Apoptosis Signal–Regulating Kinase 1 Deficiency Accelerates Hyperlipidemia-Induced Atheromatous Plaques via Suppression of Macrophage Apoptosis

OBJECTIVE—The pathogenic role of macrophage apoptosis in atherosclerosis is still debatable, but it is considered to be a suppressor of plaque progression in early stages but a promoter of plaque necrosis in advanced stages. Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays a pivotal role in stress-induced apoptosis. In the current study, we investigated the functions of ASK1 in hyperlipidemia-induced atherosclerosis. METHODS AND RESULTS—We generated ASK1 and apolipoprotein E (apoE) double-knockout mice (ASK1/apoE) and analyzed atherosclerosis in ASK1/apoE mice fed a high-cholesterol diet for 12 weeks. ASK1/apoE mice had accelerated hyperlipidemia-induced atherosclerosis, which was characterized by less apoptosis of macrophages and fewer necrotic areas, and more macrophages and elastolysis compared with apoE mice. Bone marrow transplantation from ASK1 or wild-type to apoE mice confirmed the above observation that the recipient mice of ASK1 donors had more pronounced hyperlipidemia-induced atherosclerosis than recipient mice of wild-type donors. CONCLUSION—These findings suggest that ASK1 suppresses hyperlipidemia-induced atherosclerosis via increased macrophage apoptosis and that ASK1 may cause pronounced plaque vulnerability via necrotic core development.