alexa Arginase-II induces vascular smooth muscle cell senescence and apoptosis through p66Shc and p53 independently of its L-arginine urea hydrolase activity: implications for atherosclerotic plaque vulnerability


Atherosclerosis: Open Access

Author(s): Yuyan Xiong, Yi Yu, JeanPierre Montani, Zhihong Yang, XiuFen Ming

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Background 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. Methods and Results 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. Conclusions 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.

This article was published in Journal of American Heart Association and referenced in Atherosclerosis: Open Access

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