Trimedazidine alleviates pulmonary artery banding-induced acute right heart dysfunction and activates PRAS40 in rats

// Yunshan Cao 1, 2 , Jiyang Song 1 , Shutong Shen 3 , Heling Fu 4 , Xiang Li 5 , Ying Xu 6 , Aqian Wang 1 , Xinli Li 3 and Min Zhang 7 1 Department of Cardiology, Gansu Provincial Hospital, Lanzhou 730000, China 2 Department of Heart Failure, Shanghai East Hospital, Tongji University School of Medicine, Research Center for Translational Medicine, Shanghai 200120, China 3 Department of Cardiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China 4 Animal Core Facility, Nanjing Medical University, Nanjing 210029, China 5 Department of Intensive Care, Minhang Hospital, Fudan University, Shanghai 201100, China 6 Intensive Care Unit, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China 7 Department of Pathology, Gansu Provincial Hospital, Lanzhou 730000, China Correspondence to: Yunshan Cao, email: yunshancao@126.com Min Zhang, email: sallyzhangmin@126.com Keywords: acute right dysfunction, trimedazidine, PRAS40, pulmonary artery banding Received: May 16, 2017 Accepted: August 08, 2017 Published: September 08, 2017 ABSTRACT The molecular mechanism underlying acute right heart failure (RHF) is poorly understood. We used pulmonary artery banding (PAB) to induce acute RHF characterized by a rapid rise of right ventricular pressure, and then a decrease in right ventricular pressure along with a decrease in blood pressure right after banding. We found higher brain natriuretic peptide (BNP) and beta-myosin heavy chain (βMHC) levels and lower alpha-myosin heavy chain (αMHC) levels in RHF rats than sham-operated rats. Hemodynamic indexes in rats with acute RHF were slightly improved by trimedazidine TMZ, a key inhibitor of fatty acid (FA) oxidation. TMZ also reversed downregulation of peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC-1β) and peroxisome proliferator-activated receptor alpha (PPARα) by PAB and up-regulates peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), peroxisome proliferator-activated receptor delta (PPARδ) and pyruvate dehydrogenase kinase isoform 4 (PDK4). In addition, TMZ reversed upregulation of phosphorylated Akt by PAB and increased phosphorylated proline-rich Akt-substrate 40 (PRAS40). Autophagy and apoptosis were not modified by PAB or TMZ. An acute RHF model was established in rats through 70% constriction of the pulmonary artery. TMZ treatment alleviated PAB-induced acute RHF by activating PRAS40 and upregulatingPGC-1α, PGC-1β, PPARα, PPARδ, and PDK4.