内质网应激效应分子CHOP在主动脉瓣钙化中的作用和机制研究

Aortic valve calcification (AVC) is a common clinical problem associated with increased cardiovascular events and mortality, and remains no effective therapy other than surgical replacement. Studies indicate that apoptosis and inflammation of valvular interstitial cells (VIC) play essential roles during the progression of AVC. Endoplasmic reticulum (ER) stress participates in the development of various cardiovascular diseases, but whether and how ER stress is involved in the pathogenesis of AVC remain unknown. Our preliminary inspections showed that ER stress is strongly activated in aortic valves from AVC patients and AVC rabbit model, and specific ER stress inhibitor, TUDCA, significantly suppressed the progression of AVC in rabbits. These results indicate that ER stress participates in the development of AVC. The important ER stress downstream protein, CHOP, has been documented to mediated cell apoptotic and inflammatory responses. Our preliminary studies further found CHOP activation in aortic valve tissues in AVC patients and rabbits. We therefore hypothesized that ER stress downstream protein, CHOP, positively contributes to AVC development via mediating VIC apoptosis and inflammation. To prove this hypothesis, this study will utilize ApoE and CHOP deficency mice, and primary VIC, to investigate the role and the mechanisms of ER stress downstream protein CHOP in AVC pathogenesis in both animal and cellular levels, and thus to provide a new target for AVC prevention and treatment.

主动脉瓣钙化是一种严重危害人民健康的疾病，仍缺乏有效的药物干预手段。瓣膜间质细胞凋亡和炎症在主动脉瓣钙化的发生发展中有着重要的作用，是近年研究的热点。内质网应激广泛参与许多心血管疾病的发生发展，但仍未有报道其与主动脉瓣钙化间的联系及机制。我们前期发现内质网应激在钙化性主动脉瓣狭窄患者、兔主动脉瓣钙化模型中显著激活，且内质网应激抑制剂TUDCA可显著减缓兔主动脉瓣钙化的进展，提示内质网应激参与主动脉瓣钙化的发生发展。内质网应激下游效应分子CHOP介导细胞凋亡及炎症，我们前期研究也发现CHOP在钙化性主动脉瓣狭窄和兔主动脉瓣钙化模型中显著激活。因而我们推测：内质网应激下游效应分子CHOP可能通过诱导瓣膜间质细胞凋亡和炎症，促进主动脉瓣钙化的进展。因此本项目将利用ApoE及CHOP敲除小鼠、原代瓣膜间质细胞，从动物、细胞两个层面，研究内质网应激效应分子CHOP在主动脉瓣钙化中的作用和机制。

主动脉瓣钙化是一种严重危害人民健康的疾病，仍缺乏有效的药物干预手段。瓣膜间质细胞凋亡在主动脉瓣钙化的发生发展中有着重要的作用。内质网应激CHOP通路广泛参与许多心血管疾病的发生发展，但仍未有报道其与主动脉瓣钙化间的联系及机制。我们的研究利用Apoe-/-小鼠及Apoe-/-;CHOP-/-双敲小鼠，构建主动脉瓣钙化模型，发现CHOP敲除可保护高脂饮食诱导的主动脉钙化进展，抑制主动脉瓣钙化通路激活及细胞凋亡。在原代主动脉瓣膜间质细胞中，我们发现oxLDL通过CHOP激活瓣膜间质细胞凋亡、钙化通路的激活，促进其向成骨细胞转化。利用条件培养基干预，我们进一步发现抑制CHOP保护oxLDL诱导的瓣膜间质细胞向成骨细胞分化是通过介导凋亡小体自分泌作用而实现的。本项目揭示了CHOP分子参与主动脉瓣钙化的病理生理过程，而CHOP可能成为新的主动脉瓣钙化治疗靶点。