Grant: Team Grant: Transnational Cardiovascular Research Projects

Calcific aortic valve stenosis (CAVS) is a fatal pathology that affects 2-3% of the population. Yet, drug therapies are ineffective, leaving the urgency to fully characterize the aetiology of aortic valve calcification (AVC) to develop innovative therapies. Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to and targets the low-density lipoprotein receptor (LDLR). It was recently shown that individuals with loss-of-function genetic variant at the PCSK9 gene have low levels of atherogenic lipoprotein concentrations (LDL and Lipoprotein(a)) and reduced risk of coronary heart disease and CAVS. However, the mechanisms through which altered PCSK9 activity could protect against or cause CAVS is lacking. Our preliminary data suggest that PCSK9 plays an active role in CAVS. We will, therefore, determine whether PCSK9 is a causal risk factor for CAVS using genetic epidemiology. Further, we will shed light on the molecular underpinnings through which PCSK9 causes CAVS in humans using state-of-the-art in vivo as well as in vitro models in combination with next-generation sequencing. As a complementary and potential pre-clinical model, we will determine the role of PCSK9 in the development of aortic valve calcification in mice. The overarching aim of this research program is to provide the required biological evidence using a highly translational approach to support PCSK9 as a therapeutic target for the prevention and treatment of patients with CAVS.