CatS介导的HDAC6信号通路在慢性应激性血管内膜增生中的作用及分子机制

慢性应激促进动脉粥样硬化(AS)及经皮冠状动脉介入术后再狭窄(ISR)是当今心血管领域亟需解决的难题。ISR是局部AS病变血管损伤后的一种修饰反应，主要与血管平滑肌细胞(VSMC) 增殖和迁移有关。组织蛋白酶S(CatS)通过修饰/分解各种生物活性物质调控内皮细胞的生物活性。预试验中发现慢性应激增加损伤血管CatS蛋白表达及组蛋白去乙酰化酶6(HDAC6)活性，促进VSMC增殖。本研究利用野生型、CatS基因敲除小鼠建立慢性应激模型和血管损伤模型，探讨CatS-HDAC6-JAK2-STAT3信号通路调控损伤后血管内膜增生的机制；通过基因沉默(siCatS/siHDAC6)，基因转染(ad-CatS/ad-HDAC6)，抑制剂(CatS-I/Tubastatin A)等分子生物学技术进一步探索HDAC6参与VSMC增殖和迁移的新机制，为IRS的预防和治疗以及开发新药奠定基础。

The data of recent clinical studies have prompted us to investigate the mechanisms of the chronic psychological stress-related in-stem restencois (ISR) after percutaneous coronary intervention (PCI). Restenosis is known to be a repair response to injury. Vascular media smooth muscle cell (VSMC) apoptosis and proliferation have been shown to contribute to therapeutic injury-related restenosis. Cathepsin S (CatS) is a lysosomal proteolytic protease. Recently, we found that CatS modulates VSMC proliferation via histone deacetylase 6 (HDAC6) activity. Our preliminary experiments showed that the stressed carotid arteries had increased levels of CatS expression and HDAC6 activity. Here, we applied an immobilization stress model and carotid artery injury model to study the effect of stress on CatS HDAC6 expression and activity and the injury-induced neointimal hyperplasia in wild-type (CatS+/+) mice. Next, we used CatS deficient (CatS–/–) mice and a HDAC6 specific inhibitor (tubastatin) to investigate whether CatS activity controls VSMC proliferation via the HDAC6-mediated JAK2-STAT3 signaling pathway. We also used short interfering RNA against CatS (siCatS), HDAC6 (siHDAC6), adenovirus-CatS (ad-CatS), ad-HADC6 and the proteome array to further explore the molecular mechanism underlying chronic stress-related neointima formation in mice under our experimental conditions. Thus, our results may suggest the essential role of HDAC6, activated by CatS in chronic stress-related neointimal hyperplasia in response to injury, possibly via the stimulation of the JAK2-STAT3 signaling pathway, suggesting that CatS-HDAC6 could be a novel therapeutic target for stress-related atherosclerosis-based cardiovascular disease.