Oncotarget

Research Papers:

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

Yunshan Cao _, Jiyang Song, Shutong Shen, Heling Fu, Xiang Li, Ying Xu, Aqian Wang, Xinli Li and Min Zhang

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Oncotarget. 2017; 8:92064-92078. https://doi.org/10.18632/oncotarget.20752

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Abstract

Yunshan Cao1,2, Jiyang Song1, Shutong Shen3, Heling Fu4, Xiang Li5, Ying Xu6, Aqian Wang1, Xinli Li3 and Min Zhang7

1Department of Cardiology, Gansu Provincial Hospital, Lanzhou 730000, China

2Department of Heart Failure, Shanghai East Hospital, Tongji University School of Medicine, Research Center for Translational Medicine, Shanghai 200120, China

3Department of Cardiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China

4Animal Core Facility, Nanjing Medical University, Nanjing 210029, China

5Department of Intensive Care, Minhang Hospital, Fudan University, Shanghai 201100, China

6Intensive Care Unit, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China

7Department of Pathology, Gansu Provincial Hospital, Lanzhou 730000, China

Correspondence to:

Yunshan Cao, email: [email protected]

Min Zhang, email: [email protected]

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.


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