AMP-activated protein kinase independent mechanisms of pulmonary artery banding-induced right ventricular failure

Introduction Pulmonary hypertension (PH) causes right heart failure, a devastating disease with poor survival. Right ventricular (RV) function predicts survival in PH, yet no therapies improve RV function. AMP-activated protein kinase (AMPK) is the master cellular energy sensor and its pharmacological activation is cardioprotective in left ventricular (LV) disease. Previous work from our group and others demonstrates that AMPK activation is protective in hypoxia-mediated PH and RV dysfusnction. However, hypoxia is systemic, thus the direct contributions of AMPK on RV remodeling are not fully clear. Aim We set out to determine if AMPK is protective in pulmonary artery banding (PAB)-induced RV failure, a direct surgical model of RV afterload. Methods We utilized pharmacological gain of AMPK activity (metformin) and genetic loss of AMPK through deletion of cardiac AMPKα2 (AMPK KO). Four weeks following PAB or Sham, we quantified RV remodeling by histology and echocardiography. Results PAB caused RV dysfunction at the morphological and functional level. However, neither deletion nor activation of AMPK had any impact on RV remodeling. RV mass normalized to tibia length (RV/TL; 1.5 mg/mm, 1.5 mg/mm, 1.2 mg/mm in control, metformin, and AMPK KO, respectively), RV myocyte area (302 mm 2 , 253 mm 2 , 293 mm 2 in control, metformin, and AMPK KO), and RV fractional area change (FAC; 25%, 35%, 24% in control, metformin, and AMPK KO) were similar in the presence and absence of AMPK. Conclusions AMPK in the RV seems to be neither required nor sufficient to drive PAB-induced RV failure. We suggest that mechanisms of AMPK signaling in the RV are distinct from those in the LV and hypoxia induced PH and propose that future work aim to identify additional targets for RV-centric therapy.