Abstract 19092: Endothelial Caveolin-1 Deficiency Increases Susceptibility to Lethal Heart Failure in Male Mice With Hypoxia-Induced Pulmonary Hypertension

Abstract

Introduction: Pulmonary arterial hypertension (PAH) is an incurable disease with high mortality. Reduced endothelial cell caveolin-1 (EC Cav1) expression contributes to idiopathic PAH, and in animal models, can be alleviated by inhibiting or deleting endothelial nitric oxide synthase (eNOS). Hypothesis: As females are at greater risk of developing PAH but exhibit a more favorable outcome compared to males, we hypothesized that EC Cav1 deficiency in male mice would contribute to EC Cav1-dependent sex differences following chronic hypoxia exposure. Methods: EC-Cav1 -/- mice ( Cdh5.Cre ERT2 ;mTmG;Cav1 f/f injected with tamoxifen; ECKO) vs. wild-type liter mates injected with oil (ECWT), and Cav1 KO, Cav1-RC, and WT mice (6-8 week old) were exposed to 10% O 2 for up to 8 weeks (hypoxia-induced PH (HPH)). Echocardiography, right ventricular systolic pressure (RVSP) and hypertrophy (RVH), lung histology, Western blot, and survival were used to quantify pulmonary and cardiac function. Data were analyzed by two-way ANOVA and Tukey’s post hoc analysis. Results: After 8-weeks of hypoxia exposure, over 90% of male and 40% of female Cav1 KO became moribund, whereas lethality was less than 10% for WT and Cav1 RC mice (p < 0.01). Cav1 ECKO mice exhibited 30% lethality, whereas all ECWT siblings survived. Both Cav1 KO and ECKO mice exhibited a significant increase in pulmonary artery wall thickness, RVH, and RVSP. Hypoxia also reduced PAT and TAPSE, as well as LV systolic and diastolic function, including IVRT, CO, EF, FS, and global longitudinal strain in Cav1 KO and ECKO as compared to WT, ECWT, and Cav1-RC mice indicating EC Cav1 expression is cardioprotective in the context of HPH. In whole lung lysates, we observed reduced eNOS dimerization and an increase in eNOS pSer1179 indicative of eNOS dysfunction under normoxia which was exaggerated following hypoxia exposure to a greater extent in male Cav1 KO and ECKO as compared to Cav1-RC or WT mice. Conclusions: Chronic hypoxia-induced PH and mortality observed in Cav1 KO and ECKO mice is associated with both RV and LV failure and eNOS dysfunction to a greater extent in male mice, which was largely prevented by EC Cav1 expression.