Formyl peptide receptor 2 determines sex differences in pulmonary hypertension-associated right ventricular dysfunction

Aims Pulmonary hypertension (PH) involves structural and functional changes in pulmonary vessels due to various diseases, leading to increased vascular resistance and arterial pressure. Prolonged high load gradually enlarges the right ventricle, potentially leading to right heart failure. Female patients exhibit a more favorable prognosis due to the cardioprotective effect. Formyl peptide receptor 2 (FPR2) appears to be crucial in these processes. Methods and results Here we show that FPR2 mediates sex-specific responses to SuHx(sugen5416 combined hypoxia)-induced PH in mice. Elevated RVSP and pulmonary artery remodeling were induced in both sexes during SuHx exposure, but compared with females, male mice had more severe right ventricular dysfunction (RVD). FPR2 was more highly expressed in healthy right heart from females than males, and Fpr2 deletion exacerbated RVD in SuHx-induced PH in female mice. We also found that FPR2 mediates the cardioprotective effect of estradiol in mice with PH. Data from our transcriptomics experiment further demonstrated FPR2 mediates these effects by affecting mitochondrial function and cytokines secretion from cardiomyocytes. Conclusion We demonstrate that FPR2 play an important role in mediating sex-specific responses to SuHx, thereby identifying a potential novel therapeutic target for optimizing treatment of PH and associated right heart failure. Overall design: RNA-Seq analysis of right ventricles from 8-week-old female WT and Fpr2-KO mice under baseline conditions and after 3 weeks of SuHx exposure.