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• W1985939862 abstract "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 VSMC s with respect to plaque vulnerability is unknown. This study investigated the functions of Arg‐II in VSMC s linking to plaque vulnerability. Methods and Results In vitro studies were performed on VSMC s isolated from human umbilical veins, whereas in vivo studies were performed on atherosclerosis‐prone apolipoprotein E‐deficient (ApoE −/− ) mice. In nonsenescent VSMC s, 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 ( ERK s) and sequential activation of 40S ribosomal protein S6 kinase 1 (S6K1)—c‐Jun N‐terminal kinases (JNKs). In senescent VSMC s, 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 VSMC s 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." @default.
• W1985939862 created "2016-06-24" @default.
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• W1985939862 date "2013-08-22" @default.
• W1985939862 modified "2023-10-06" @default.
• W1985939862 title "Arginase‐II Induces Vascular Smooth Muscle Cell Senescence and Apoptosis Through p66Shc and p53 Independently of Its <scp>l</scp> ‐Arginine Ureahydrolase Activity: Implications for Atherosclerotic Plaque Vulnerability" @default.
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• W1985939862 doi "https://doi.org/10.1161/jaha.113.000096" @default.
• W1985939862 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3828809" @default.
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