Critical and diverse in vivo roles of apoptosis signal-regulating kinase 1 in animal models of atherosclerosis and cholestatic liver injury.

Apoptosis plays pivotal in vivo roles in not only vital processes, such as cell turnover and embryonic development, but also various inflammatory disorders. However, the role of apoptosis by vascular and hepatic cells in the respective progression of atherosclerosis and liver injury remains controversial. Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase family member that is activated through distinct mechanisms in response to various cytotoxic stressors. ASK1, ubiquitously expressed, is situated in an important upstream position for many signal transduction pathways, which subsequently induce inflammation and/or apoptosis. Our serial in vivo studies have uniquely reported that the expression of phosphorylated ASK1 is variably seen in atherosclerotic lesions or bile-duct-ligation (BDL)-induced injury livers. In mice genetically deficient of ASK1 (ASK1⁻/⁻), activated ASK1 signaling accelerates high-cholesterol-diet-induced necrotic lipid core formation by inducing macrophage apoptosis and enhances ligation injury-induced vascular remodeling via pro-inflammatory reactions and by stimulating apoptosis of smooth muscle cells. In contrast, in models of BDL-induced cholestatic liver injury, the pathogenic roles of ASK1-mediated early necro-inflammation, but not apoptosis, and the proliferation of hepatocytes and cholangiocytes are crucial in subsequent peribiliary fibrosis/fibrogenesis. These animal models of acute to chronic inflammatory diseases show that stimulated ASK1 signaling critically and diversely regulates not only hypercholesterolemia-induced atherosclerosis and injury-induced arteriosclerosis, but also the acute and subacute-to-chronic phase of BDL-induced cholestasis. We herein review the diverse, key in vivo roles of ASK1 signaling in the pathogenesis of inflammatory disorders closely related to metabolic syndrome.