Arginase-II induces vascular smooth muscle cell senescence and apoptosis through p66Shc and p53 independently of its l-arginine ureahydrolase activity: implications for atherosclerotic plaque vulnerability.

Vascular smooth muscle cell (vsmc) senescence and apoptosis are involved in atherosclerotic plaque vulnerability. arginase-ii (arg-ii) has been shown to promote vascular dysfunction and plaque vulnerability phenotypes in mice through uncoupling of endothelial nitric oxide synthase and activation of macrophage inflammation. the function of arg-ii in vsmcs with respect to plaque vulnerability is unknown. this study investigated the functions of arg-ii in vsmcs linking to plaque vulnerability. in vitro studies were performed on vsmcs isolated from human umbilical veins,whereas in vivo studies were performed on atherosclerosis-prone apolipoprotein e-deficient (apoe(-/-)) mice. in nonsenescent vsmcs,overexpressing wild-type arg-ii or an l-arginine ureahydrolase inactive arg-ii mutant (h160f) caused similar effects on mitochondrial dysfunction,cell apoptosis,and senescence,which were abrogated by silencing p66shc or p53. the activation of p66shc but not p53 by arg-ii was dependent on extracellular signal-regulated kinases (erks) and sequential activation of 40s ribosomal protein s6 kinase 1 (s6k1)-c-jun n-terminal kinases (jnks). in senescent vsmcs,arg-ii and s6k1,erk-p66shc,and p53 signaling levels were increased. silencing arg-ii reduced all these signalings and cell senescence/apoptosis. conversely,silencing p66shc reduced erk and s6k1 signaling and arg-ii levels and cell senescence/apoptosis. furthermore,genetic ablation of arg-ii in apoe(-/-) mice reduced the aforementioned signaling and apoptotic vsmcs in the plaque of aortic roots. arg-ii,independently of its l-arginine ureahydrolase activity,promotes mitochondrial dysfunction leading to vsmc senescence/apoptosis through complex positive crosstalk among s6k1-jnk,erk,p66shc,and p53,contributing to atherosclerotic vulnerability phenotypes in mice.