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目的:平滑肌蛋白22α(smooth muscle protein 22α,SM22α)被视为是细胞衰老的标志物,但是其在血管平滑肌细胞(vascular smooth muscle cell,VSMC)衰老过程中的作用尚不清楚。本研究旨在探讨SM22α在VSMC衰老和血管老化进程中的作用。方法:利用angiotensin Ⅱ(Ang Ⅱ,10-7mol/L)慢性刺激诱导VSMC衰老;用野生型和SM22α基因敲除小鼠皮下植泵,持续灌注Ang Ⅱ(1μg·kg-1·min-1)4周,复制高血压模型。通过敲低和过表达SM22α观察其对VSMC衰老及调控通路蛋白表达和活性的影响。结果:Ang Ⅱ持续刺激可诱导VSMC衰老,伴随着SM22α的表达增高。敲低SM22α可减弱Ang Ⅱ诱导的VSMC衰老,过表达则反之。在Ang Ⅱ诱导VSMC衰老条件下,SM22α表达上调抑制Mdm2与p53的结合,上调p53含量。SM22α表达增加抑制Akt与Mdm2的磷酸化活化,导致Mdm2与p53的结合减弱。SM22α基因敲除改善Ang Ⅱ诱导的主动脉VSMC衰老和血压升高。结论:SM22α表达上调抑制Akt/Mdm2通路激活,进而减弱Mdm2与p53的结合,上调p53的表达量,促进衰老。
OBJECTIVE: Smooth muscle protein 22α (SM22α) is considered as a marker of cellular senescence, but its role in the process of aging of vascular smooth muscle cells (VSMC) remains unclear. This study aimed to investigate the role of SM22α in VSMC aging and vascular aging. Methods: Aging VSMCs were induced by chronic stimulation with angiotensin Ⅱ (Ang Ⅱ, 10-7mol / L). Ang Ⅱ (1μg · kg-1 · min-1) 4 weeks, copy the model of hypertension. The knockdown and overexpression of SM22α were used to observe the effect on the expression of VSMCs and the regulation of the protein expression and activity of VSMCs. Results: Continuous stimulation with Ang Ⅱ induced the VSMC senescence accompanied with the increase of SM22α expression. Knockdown of SM22α attenuated the senescence of VSMCs induced by Ang Ⅱ, whereas the overexpression of SM22α decreased the expression of SM22α. Under the condition of Ang Ⅱ induced VSMC aging, up-regulation of SM22α inhibited the binding of Mdm2 to p53 and up-regulated the content of p53. Increased expression of SM22α inhibits the phosphorylation of Akt and Mdm2, resulting in a decrease in the binding of Mdm2 to p53. SM22α gene knockdown improves Ang Ⅱ induced aortic VSMC aging and elevated blood pressure. Conclusion: The up - regulation of SM22α can inhibit the activation of Akt / Mdm2 pathway, further weaken the binding of Mdm2 to p53, increase the expression of p53 and promote the senescence.