Loss of Hypoxia Inducible Factor‐1α Increases Right Ventricular Hypertrophy in Chronic Hypoxia‐Induced Pulmonary Hypertension

Abstract

Pulmonary hypertension (PH) is a risk factor for right ventricular (RV) hypertrophy and right heart failure in patients with congenital heart disease, chronic obstructive pulmonary disease, interstitial lung diseases, and obstructive sleep apnea. Chronic alveolar hypoxia (CH) in these diseases promotes sustained pulmonary vasoconstriction and pulmonary artery (PA) remodeling resulting in the development of PH. Patient outcome, however, is often determined by the response of the RV to increased afterload caused by increased PA resistance. Little is known about the cellular and molecular mechanisms involved in RV hypertrophy associated with PH, which begins as compensated hypertrophy but can progress to dilated, decompensated RV failure, and death. Recently, we have shown that loss of hypoxia inducible factor 1 alpha (HIF‐1α) in PA smooth muscle cell (PASMC) attenuates PA remodeling and the increase in RV systolic pressure (RVSP) induced by CH but fails to attenuate RV remodeling. This suggests that CH directly regulates RV remodeling independently from PH and increased RVSP. Therefore, we aimed to determine the role of HIF‐1α in RV remodeling in CH‐induced PH. Genetic deletion of HIF‐1α from smooth muscle (SM) was achieved by breeding SM‐heavy myosin chain‐Cre expressing mice (SMC) with HIF‐1αflox/flox mice to generate SMC‐HIF‐1αflox/flox mice. Genetic deletion of HIF‐1α from cardiomyocytes was achieved by breeding cardiac‐specific alpha myosin‐heavy chain‐Cre expressing mice (Myh6Cre) with HIF‐1αflox/flox mice to generate Myh6Cre‐HIF‐1αflox/flox mice. A double SM and cardiomyocyte knockout was also generated by crossing SMC‐HIF‐1αflox/flox with Myh6Cre‐HIF‐1αflox/flox mice to generate SMC‐Myh6Cre‐HIF‐1αflox/flox mice. Tamoxifen was administered i.p. to activate Cre‐mediated excision of the HIF‐1α gene in targeted cells of adult mice. Wildtype, SMC‐, Myh6Cre‐ and SMC‐Myh6Cre‐HIF‐1α‐depleted mice were then housed under normoxia or CH (10% O2) for four weeks. CH increased RVSP and RV remodeling in wildtype mice. Loss of HIF‐1α in SMC‐HIF‐1α or SMC‐Myh6Cre‐HIF‐1α attenuated the CH‐induced increase in RVSP, but did not alter RV remodeling. Interestingly, the deletion of HIF‐1α from cardiomyocytes (Myh6Cre‐HIF‐1α) increased RV hypertrophy compared to wildtype mice in CH while having no effect on RVSP. These data suggest that HIF‐1α regulates RV remodeling and that loss of HIF‐α in cardiomyocytes results in unregulated cardiac remodeling during CH. Understanding the role of HIF‐1α in RV remodeling in PH may provide therapeutic targets for the development of improved treatment strategies for patients with PH.Support or Funding InformationSupported by NIH Grants HL35440 and HL122062 (PTS) and Parker B. Francis Fellowship (KAS)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.