Cardiomyocyte‐specific Deletion of AMP‐activated Protein Kinase Exacerbates Right Ventricular Dysfunction in Pulmonary Hypertension

Abstract

Right ventricular (RV) dysfunction dictates survival in aged-related left –heart failure and pulmonary hypertension (PH), yet RV remodeling is poorly understood and no RV directed therapies exist. Our group previously reported that metformin, an AMP-activated protein kinase (AMPK) activator, protects against PH-induced RV dysfunction, yet the mechanisms of metformin-mediated protection are unclear. The objective of this study was to elucidate the role of cardiac AMPK in PH-RV dysfunction and whether AMPK is required for the cardioprotective effects of metformin. We used Cre-Lox recombination techniques to delete AMPKα2 temporally and selectively from cardiomyocytes before placing male and female AMPK deleted (KO) and wild type (WT) C57Bl6 mice in a hypobaric hypoxia (HH) chamber (~17,000ft) for 4 weeks with and without metformin (200mg/kg/day). HH exposure induced cardiopulmonary remodeling as evidenced by higher lung and RV weights as well as lower RV fractional area change, pulmonary acceleration time (PAT), stroke volume (SV) and cardiac output (CO). HH-induced cardiopulmonary remodeling was exacerbated in males compared to females, consistent with previous reports of sex differences in this model. Deletion of AMPK resulted in higher RV weights normalized to TL (RV/TL) even in control conditions, with male KO AMPK mice undergoing significantly worse RV remodeling in response to HH than females. Interestingly, deletion of cardiac-specific AMPK also impacts lung remodeling. AMPK KO male and female mice demonstrated higher lung weights than WT in control mice and AMPK KO exacerbated lung remodeling in HH. Together, we suggest that AMPK is critical in the RV and PH-RHF. Ongoing work will determine if cardiac-specific AMPK is required for metformin-mediated protection in PH-RHF.