Abstract 14869: The Role of Female Sex Hormones in Dimorphism of the Immune System in Group 1 Pulmonary Hypertension

Abstract

Background: The right ventricle (RV) fails in pulmonary arterial hypertension (PAH) in part due to inflammation. In male PAH, RV CCR2 + macrophages induce inflammation via NLRP3 inflammasome. Since PAH males have worse outcomes, a cardioprotective role of the female sex hormones is suggested. Hypothesis: Ovariectomy (OVX) in females recapitulates the males’ disease severity by increasing RV inflammation. NLRP3 inhibition ameliorates RV function in male and OVX rats with monocrotaline (MCT)-induced PAH. Methods: PAH was induced with MCT (60mg/kg) in male, female, and OVX female Sprague Dawley rats. 10 days post-MCT, rats (n=6/sex) were treated with the NLRP3 inhibitor, MCC950 (6mg/Kg/day). Control and MCT rats were studied (n=4/sex/group). RV function was assessed by echocardiography and high-fidelity hemodynamics. Inflammatory (His48 lo CD43 lo CCR2 + ) monocytes were quantified via flow cytometry, RV macrophages (CD68 + CCR2 + ) and mitochondrial morphology were quantified by confocal microscopy. RV fibrosis and hypertrophy were measured. Results: MCT rats had higher RV systolic pressure (RVSP), reduced pulmonary artery acceleration time (PAAT), cardiac output (CO), and tricuspid annular plane systolic excursion (TAPSE) vs. controls (Table). The RV end-diastolic pressure (RVEDP) was high in MCT males, while RV-free wall thickening was reduced in males and OVX. MCC950 improved CO in MCT males but reduced RVSP in males and OVX. The number of CCR2 + inflammatory monocytes ( p=0.065 ) and RV macrophages ( p=0.007 ) was higher in MCT males. Fragmented mitochondria ( p=0.004 ), RV fibrosis ( p<0.0001) and cardiomyocyte hypertrophy ( p<0.0001 ) were present only in MCT males. MCC950 reduced fibrosis ( p=0.006 ) and hypertrophy ( p<0.0001) in males. MCC950 tended to improve hemodynamics in OVX. Conclusion: RV inflammation is most severe in males, and female sex hormones are cardioprotective. Inhibition of the NLRP3 is beneficial in MCT males and trend to benefit OVX.