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Objective-: Smooth muscle (SM) 22[alpha], an actin-binding protein, displays an upregulated expression as a marker during cellular senescence. However, the causal relationship between SM22[alpha] and senescence is poorly understood. This study aimed to investigate the role of SM22[alpha] in angiotensin II (Ang II)-induced senescence of vascular smooth muscle cells (VSMCs).

Approach and Results-: We prepared a model of VSMC senescence induced by Ang II and found that the expression of SM22[alpha] in VSMCs was increased in response to chronic Ang II treatment. Overexpression of SM22[alpha] promoted Ang II-induced VSMC senescence, whereas knockdown of SM22[alpha] suppressed this process. Moreover, this effect of SM22[alpha] was p53 dependent. Increased SM22[alpha] protein obstructed ubiquitination and degradation of p53 and subsequently improved its stability. Furthermore, SM22[alpha] inhibited phosphorylation of Mdm2 (mouse double minute 2 homolog), an E3 ubiquitin-protein ligase, accompanied by a decreased interaction between Mdm2 and p53. Using LY294002, a PI3K/Akt inhibitor, we found that PI3K/Akt-mediated Mdm2 phosphorylation and activation was inhibited in senescent or SM22[alpha]-overexpressed VSMCs, in parallel with decreased p53 ubiquitination. We further found that SM22[alpha] inhibited activation of PI3K/Akt/Mdm2 pathway via strengthening actin cytoskeleton. In the in vivo study, we showed that the disruption of SM22[alpha] reduced the increase of blood pressure induced by Ang II, associated with decreased VSMC senescence through a mechanism similar to that in VSMCs in vitro.

Conclusions-: In conclusion, these findings suggest that the accumulation of SM22[alpha] promotes Ang II-induced senescence via the suppression of Mdm2-mediated ubiquitination and degradation of p53 in VSMCs in vitro and in vivo.

(C) 2017 American Heart Association, Inc.