Cardiac AMPK is not required for cardioprotection by metformin in pulmonary hypertension induced right heart failure

Abstract

Right ventricle (RV) dysfunction dictates survival in pulmonary hypertension (PH) and other clinical conditions. Metformin, a clinically relevant AMP activated protein kinase (AMPK) activator, has been proposed as a therapy for PH induced right heart failure (PH‐RHF) due to its well‐reported cardioprotective properties. Indeed, our group has recently shown that metformin is protective in PH‐RHF, but the mechanisms of protection in the RV remain unknown. The objective of this study was to use determine whether the protective properties of metformin require cardiac AMPK. We used Cre‐Lox recombination to create a cardiomyocyte specific AMPK deleted with temporal regulation of expression. AMPK knockout (KO) and wild type (WT) control mice were placed in a hypobaric hypoxia (HH) chamber (~17,000ft) for 4 weeks to induce PH‐RHF, with or without metformin (200mg/kg/day) in drinking water. Cardiomyocyte specific AMPK deletion exacerbated RV and LV remodeling in response to HH compared to WT, with significant sex differences evidenced by males undergoing worse remodeling than females. AMPK deletion exacerbated cardiac output and RV stroke volume compared to WT mice. Metformin rescued cardiac remodeling in male KO mice but did not attenuate remodeling in female mice. We suggest that metformin is a potential therapeutic target to attenuate maladaptive cardiac remodeling induced by PH‐RHF, but only in male mice. Metformin does not require cardiac AMPK for cardioprotection. The mechanisms by which metformin affords protection in PH‐RHF are still unclear, but may include AMPK activity in non‐myocyte cell populations. Ongoing work will elucidate the role of AMPK activation in fibroblasts as well as other systemic and cardiac mechanisms which may explain how metformin protects against PH‐RHF.