Zhang Wen-Mei, Liu Yan, Li Tao-Tao, Piao Chun-Mei, Liu Ou, Liu Jun-Ling, Qi Yong-Fen, Jia Li-Xin, Du Jie
Beijing Anzhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart, Lung & Blood Vessel Disease, Beijing 100029, China.
School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China.
J Mol Cell Cardiol. 2016 Oct;99:76-86. doi: 10.1016/j.yjmcc.2016.08.008. Epub 2016 Aug 14.
Thoracic aortic aneurysm/dissection (TAAD) is characterized by excessive smooth muscle cell (SMC) loss, extracellular matrix (ECM) degradation and inflammation. However, the mechanism whereby signaling leads to SMC loss is unclear. We used senescence-associated (SA)-β-gal staining and analysis of expression of senescence-related proteins (p53, p21, p19) to show that excessive mechanical stretch (20% elongation, 3600cycles/h, 48h) induced SMC senescence. SMC senescence was also detected in TAAD specimens from both mice and humans. High-performance liquid chromatography and luciferin-luciferase-based assay revealed that excessive mechanical stretch increased adenosine diphosphate (ADP) release from SMCs both in vivo and in vitro. Elevated ADP induced SMC senescence while genetic knockout of the ADP receptor, P2Y G protein-coupled receptor 12 (P2ry12), in mice protected against SMC senescence and inflammation. Both TAAD formation and rupture were significantly reduced in P2ry12 mice. SMCs from P2ry12 mice were resistant to senescence induced by excessive mechanical stretch or ADP treatment. Mechanistically, ADP treatment sustained Ras activation, whereas pharmacological inhibition of Ras protected against SMC senescence and reduced TAAD formation. Taken together, excessive mechanical stress may induce a sustained release of ADP and promote SMC senescence via P2ry12-dependent sustained Ras activation, thereby contributing to excessive inflammation and degeneration, which provides insights into TAAD formation and progression.
胸主动脉瘤/夹层（TAAD）的特征是平滑肌细胞（SMC）过度丢失、细胞外基质（ECM）降解和炎症。然而，信号传导导致SMC丢失的机制尚不清楚。我们使用衰老相关（SA）-β-半乳糖苷酶染色和衰老相关蛋白（p53、p21、p19）表达分析表明，过度机械拉伸（20%伸长、3600次循环/小时、48小时）可诱导SMC衰老。在小鼠和人类的TAAD标本中也检测到了SMC衰老。高效液相色谱法和基于荧光素-荧光素酶的检测显示，过度机械拉伸在体内和体外均增加了SMC中ADP的释放。ADP升高诱导SMC衰老，而小鼠中ADP受体P2Y G蛋白偶联受体12（P2ry12）的基因敲除可防止SMC衰老和炎症。P2ry12基因敲除小鼠的TAAD形成和破裂均显著减少。P2ry12基因敲除小鼠的SMC对过度机械拉伸或ADP处理诱导的衰老具有抗性。从机制上讲，ADP处理持续激活Ras，而Ras的药理学抑制可防止SMC衰老并减少TAAD形成。综上所述，过度机械应力可能诱导ADP持续释放，并通过P2ry12依赖的Ras持续激活促进SMC衰老，从而导致过度炎症和退变增加，这为TAAD的形成和进展提供了见解。
