The adiponectin receptor system as new target for prevention and therapy of calcific aortic valve disease

主动脉瓣钙化病（CAVD）是最常见的获得性心脏瓣膜疾病。一种主要的疾病模式是主动脉瓣狭窄，其标志是瓣膜开口狭窄，增加了对心脏血液流动的阻力。相关的心壁压力增加引发代偿性肥厚重构，长期失代偿最终导致不可逆的心力衰竭。从机制上讲，CAVD是一个积极的、多方面的过程，涉及脂蛋白沉积、慢性炎症、间质细胞成骨分化以及小叶纤维化和钙化。年龄增长、男性、高血压和遗传倾向已被确定为危险因素。代谢性疾病，如肥胖、2型糖尿病和代谢综合征，进一步增加了冠心病的风险。由于其复杂的发病机制，目前尚无基于药物的CAVD治疗方法，手术置换狭窄的主动脉瓣是唯一有效的治疗选择。脂肪因子脂联素及其受体AdipoR1、AdipoR2和T-cadherin构成了一个具有保护性代谢、免疫调节、抗纤维化和抗钙化作用的系统。代谢紊乱（如肥胖、2型糖尿病和代谢综合征）的慢性低度全身性炎症通常会引发脂联素和AdipoR1/R2表达的下调。在本项目的准备工作中，我们测量了人主动脉瓣活检组织中AdipoR1/R2和T-cadherin的mRNA表达水平，显示正常、纤维化和钙化的形态表型作为CAVD的连续分期。分析显示，与正常主动脉瓣相比，纤维化和钙化主动脉瓣中AdipoR1/R2和T-cadherin的表达水平降低，并随着CAVD发病的进展而降低。有趣的是，cavd相关的瓣膜AdipoR1/R2和T-cadherin表达下调与2型糖尿病作为代谢合并症无关，即非糖尿病患者也存在这种联系。这些结果为脂联素受体系统的瓣膜表达与CAVD发病机制之间提供了明确的描述性联系。因此，本项目旨在通过对人主动脉瓣microRNA的表达谱分析，以及对绵羊瓣膜间质细胞和组织的2D和3D CAVD模型进行体外实验，来确定同时驱动CAVD发病和抑制脂联素受体系统的病因因素。此外，本项目旨在分析脂联素受体系统是否可以作为预防或治疗CAVD的新靶点。我们的假设是，某些microrna抑制脂联素受体系统，从而促进CAVD的发病机制。因此，沉默这些microrna的拮抗剂与脂联素受体激动剂联合应用为预防和治疗CAVD提供了新的选择。

Calcific aortic valve disease (CAVD) is the most frequent acquired heart valve disease. A major disease pattern is aortic stenosis which is marked by a narrowed valve opening area raising the resistance towards the blood flow from the heart. The associated increase in cardiac wall stress triggers compensatory hypertrophic remodelling which decompensates in the long term finally resulting in irreversible heart failure. Mechanistically, CAVD is an active and multifaceted process involving lipoprotein deposition, chronic inflammation, osteoblastic differentiation of interstitial cells as well as leaflet fibrosis and calcification. Increasing age, male sex, hypertension and genetic predispositions have been identified as risk factors. Metabolic disorders such as obesity, diabetes type 2 and metabolic syndrome further increase the CAVD risk. Due to the complex pathogenesis there is currently no drug-based CAVD therapy available, i.e. surgical replacement of stenotic aortic valves is the only effective therapeutic option.The adipokine adiponectin and its receptors AdipoR1, AdipoR2 and T-cadherin constitute a system exerting protective metabolic, immunomodulatory, anti-fibrotic and anti–calcific effects. Chronic low-grade systemic inflammation in context of metabolic disorders such as obesity, diabetes type 2 and metabolic syndrome typically triggers a downregulation of adiponectin and AdipoR1/R2 expression. In preparation of this project mRNA expression levels of AdipoR1/R2 and T-cadherin were measured in human aortic valve biopsies displaying normal, fibrotic and calcified morphological phenotypes as consecutive stages of CAVD. The analysis revealed that expression levels of AdipoR1/R2 and T-cadherin are diminished in fibrotic and calcified aortic valves compared to their normal counterparts and tend to decrease with proceeding CAVD pathogenesis. Interestingly, the CAVD-associated downregulation of valvular AdipoR1/R2 and T-cadherin expression is independent of diabetes type 2 as metabolic comorbidity, i.e. the connection also exists for non-diabetic patients. These results provide a clear descriptive link between valvular expression of the adiponectin receptor system and CAVD pathogenesis. Thus, employing a microRNA expression profiling in human aortic valves and in vitro-experiments in 2D and 3D CAVD models working with ovine valvular interstitial cells and tissue, respectively, the project is designed to identity the aetiological factors simultaneously driving CAVD pathogenesis and suppressing the adiponectin receptor system. Moreover, the project aims to analyse whether the adiponectin receptor system can be used as a new target for prevention or therapy of CAVD. Our hypothesis is that certain microRNAs suppress the adiponectin receptor system thus contributing to CAVD pathogenesis. Hence, antagomirs silencing these microRNAs applied in combination with adiponectin receptor agonists offer new options for prevention and therapy of CAVD.