瓣膜内皮细胞衰老对退行性心脏瓣膜病的作用及机制研究

退行性心脏瓣膜病（DVHD）是我国最常见的老年瓣膜疾病，发生机制尚未完全阐明。该病发病隐匿，出现临床症状时病情已较严重，大多数需行瓣膜置换手术，给人类身心健康带来巨大威胁，故积极探索DVHD发病机制，实现早期预防与治疗则尤为重要。瓣膜内皮细胞(VEC)和间质细胞(VIC)在DVHD发生中扮演重要角色，而衰老是DVHD相关突出危险因素。我们已有研究发现，主动脉瓣狭窄患者瓣膜组织中炎性因子升高及Hippo通路活性改变；进一步研究发现衰老VEC培养液上清中TNF-α升高，并诱导VIC中YAP表达上调及成骨样变。因此我们推测VEC衰老并通过衰老相关分泌表型改变瓣膜局部微环境，改变VIC中Hippo通路活性，导致细胞成骨样分化。本项目针对此可能，研究VEC衰老及衰老细胞清除在DVHD发生发展中的作用，明确VEC对VIC的调控作用及诱导VIC成骨样分化的分子机制，为预防和治疗DVHC提供新思路和方法。

Degenerative valvular heart disease(DVHD) is the most common valvular disease among the elderly in China. However, its pathogenesis still remains incompletely clear. The disease shows no symptoms during early development. However, it has developed to be relatively critical once there are symptoms. Under such circumstances, valve replacement operation is necessary for most patients, which will seriously threatening mental and physical health of patients. In view of this, it’s quite important to ascertain DVHD pathogenesis, so as to prevent and control the disease before and during early development. Valve endothelial cells(VEC) and valvular interstitial cells(VIC) play a significant role in DVHD development and senility comes as an obviously risky factor of DVHD. According to our studies, there is rise in inflammatory factors and changed Hippo pathway activity in valvular tissues of patients with aortic valve stenosis. Further studies show there is rise in TNF-α in senescent VEC culture media supernatant. Besides, it will induce expression up-regulation and osteoid progress of YAP in VIC. Therefore, we conjecture VEC senescence, which changes valvular local micro-environment and Hippo pathway activity in VIC through senility-related secretory phenotype; as a result, osteoid progress occurs to cells. For such possibility, the research project is designed to study the role that VEC senility and senescent cell clearance play in DVHD development and progress. This way, it aims to ascertain the regulatory effects of VEC on VIC and its molecular mechanism where VEC induces osteoid progress of VIC, in an effort to open up new ideas and methods for DVHD prevention and treatment.