| First Author | Miao SB | Year | 2017 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 37 |
| Issue | 10 | Pages | 1849-1859 |
| PubMed ID | 28798142 | Mgi Jnum | J:269230 |
| Mgi Id | MGI:6272142 | Doi | 10.1161/ATVBAHA.117.309378 |
| Citation | Miao SB, et al. (2017) Accumulation of Smooth Muscle 22alpha Protein Accelerates Senescence of Vascular Smooth Muscle Cells via Stabilization of p53 In Vitro and In Vivo. Arterioscler Thromb Vasc Biol 37(10):1849-1859 |
| abstractText | OBJECTIVE: Smooth muscle (SM) 22alpha, an actin-binding protein, displays an upregulated expression as a marker during cellular senescence. However, the causal relationship between SM22alpha and senescence is poorly understood. This study aimed to investigate the role of SM22alpha 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 SM22alpha in VSMCs was increased in response to chronic Ang II treatment. Overexpression of SM22alpha promoted Ang II-induced VSMC senescence, whereas knockdown of SM22alpha suppressed this process. Moreover, this effect of SM22alpha was p53 dependent. Increased SM22alpha protein obstructed ubiquitination and degradation of p53 and subsequently improved its stability. Furthermore, SM22alpha 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 SM22alpha-overexpressed VSMCs, in parallel with decreased p53 ubiquitination. We further found that SM22alpha inhibited activation of PI3K/Akt/Mdm2 pathway via strengthening actin cytoskeleton. In the in vivo study, we showed that the disruption of SM22alpha 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 SM22alpha promotes Ang II-induced senescence via the suppression of Mdm2-mediated ubiquitination and degradation of p53 in VSMCs in vitro and in vivo. |
