Investigating the cardio-metabolic functions of the coagulation factor receptors PAR1 and PAR2

In addition to their key role in haemostasis, the coagulation factors thrombin and the activated factor-X (FXa) exert direct effects in various cell types via activation of the protease-activated-receptors PAR1 and PAR2. In previous studies, we have shown that reduced levels of cardiac PAR2 expression in patients with heart failure with preserved ejection fraction (HFpEF) are associated with aggravated diastolic dysfunction and myocardial fibrosis. Consistently, the lack of PAR2 expression in a murine model of genetic PAR2-deficiency resulted in cardiac fibrosis and diastolic dysfunction (Friebel et al., 2019). Interestingly, PAR2-deficiency was associated with increased cardiac expression of PAR1 and treatment with the PAR1 antagonist vorapaxar significantly reduced cardiac fibrosis and inflammation in the metabolic disease model of apolipoprotein E (ApoE)-deficient mice. However, to date unknown is the role and functional interaction of both PAR1 and PAR2 under conditions of metabolic challenge. Therefore, we generated an ApoE-PAR2-double deficient mouse model. Goal of the contracted research is to investigate if a pharmacological PAR1 inhibition can modify metabolic and cardiac functions in this model. The specific aims of the project are to determine: 1) any effect of PAR1 antagonism on lipid metabolism and glucose parameters in ApoE and ApoE-PAR2 mice, 2) if expression profiles of proinflammatory and prothrombotic genes are modified, and 3) if PAR-1 inhibition modulates cardiac and characteristic metabolic parameters as well as thrombus formation in these disease models.