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

钙化性主动脉瓣疾病（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，其特征在于瓣膜开口面积变窄，从而提高了对来自心脏的血流的阻力。心壁应力的相关增加触发代偿性肥大重塑，其在长期内失代偿，最终导致不可逆的心力衰竭。从机制上讲，CAVD是一个活跃的多方面过程，涉及脂蛋白沉积、慢性炎症、间质细胞的成骨细胞分化以及瓣叶纤维化和钙化。年龄增长、男性、高血压和遗传倾向已被确定为风险因素。代谢紊乱如肥胖、2型糖尿病和代谢综合征进一步增加CAVD风险。由于CAVD发病机制复杂，目前尚无药物治疗，即狭窄主动脉瓣的外科置换术是唯一有效的治疗选择，脂联素及其受体AdipoR 1、AdipoR 2和T-cadherin构成了一个系统，发挥保护代谢、免疫调节、抗纤维化和抗钙化作用。在代谢紊乱如肥胖、2型糖尿病和代谢综合征的背景下，慢性低度全身性炎症通常触发脂联素和AdipoR 1/R2表达的下调。在本项目的准备中，在显示正常、纤维化和钙化形态表型作为CAVD连续阶段的人主动脉瓣活检中测量AdipoR 1/R2和T-钙粘蛋白的mRNA表达水平。分析显示，AdipoR 1/R2和T-cadherin的表达水平在纤维化和钙化的主动脉瓣中与其正常对应物相比减少，并且随着CAVD发病机制的进行而趋于减少。有趣的是，CAVD相关的瓣膜AdipoR 1/R2和T-cadherin表达下调与2型糖尿病代谢合并症无关，即非糖尿病患者也存在这种联系。这些结果提供了脂联素受体系统的瓣膜表达和CAVD发病机制之间的明确描述性联系。 因此，采用人主动脉瓣中的microRNA表达谱以及分别使用绵羊瓣膜间质细胞和组织的2D和3D CAVD模型中的体外实验，该项目旨在识别同时驱动CAVD发病机制和抑制脂联素受体系统的病因学因素。此外，该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，从而有助于CAVD的发病机制。因此，与脂联素受体激动剂组合应用的沉默这些microRNA的阿托洛尔为预防和治疗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.