Role of Hypoxia-Inducible Factors in Regulating Right Ventricular Function and Remodeling during Chronic Hypoxia-Induced Pulmonary Hypertension.

Pulmonary hypertension (PH) and right ventricular (RV) hypertrophy frequently develop in patients with hypoxic lung disease. Chronic alveolar hypoxia (CH) promotes sustained pulmonary vasoconstriction and pulmonary artery (PA) remodeling by acting on lung cells, resulting in the development of PH. RV hypertrophy develops in response to PH, but arterial hypoxemia in CH may influence that response by activating Hypoxia-Inducible Factor-1α (HIF-1α) and/or HIF-2α in cardiomyocytes. Indeed, other studies show that attenuation of PH in CH fails to prevent RV remodeling, suggesting that PH-independent factors regulate RV hypertrophy. Therefore, we examined the role of HIFs in RV remodeling in CH-induced PH. We deleted HIF-1α and/or HIF-2α in hearts of adult mice that were then housed under normoxia or CH (10% O2) for 4 weeks. RNA-seq analysis of the RV revealed that HIF-1α and HIF-2α regulate the transcription of largely distinct gene sets during CH. RV systolic pressure (RVSP) increased and RV hypertrophy developed in CH. Deletion of HIF-1α in smooth muscle attenuated the CH-induced increases in RVSP but did not decrease hypertrophy. Deletion of HIF-1α in cardiomyocytes amplified RV remodeling; this was abrogated by simultaneous loss of HIF-2α. CH decreased stroke volume and cardiac output in WT but not in HIF-1α-deficient hearts, suggesting that CH may cause cardiac dysfunction via HIF-dependent signaling. Collectively, these data reveal that HIF-1 and HIF-2 act together in RV cardiomyocytes to orchestrate RV remodeling in CH, with HIF-1 playing a protective role rather than driving hypertrophy.