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

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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.