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.
Highlights
Acute right heart failure (RHF) is a common but rarely studied disease that might be caused by rapidly increased right ventricle (RV) afterload during acute pulmonary embolism, hypoxic pulmonary vasoconstriction, or after cardiac transplantation or prolonged cardiopulmonary bypass
Our previous study found that phosphorylated Akt strongly expressed in the threonine 308 site but not in the serine 473 site in the RV compared with the left ventricle (LV), and proline-rich Akt-substrate 40 (PRAS40), an indicator of Akt activity, was significantly increased in its phosphorylated form but total prolinerich Akt-substrate 40 (PRAS40) was not increased in the RV compared with the LV [11]
We found that Akt activity was increased and peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC-1β) and peroxisome proliferator-activated receptor alpha (PPARα) were decreased in rats with pulmonary artery banding (PAB) compared with rats in the sham group
Summary
Acute right heart failure (RHF) is a common but rarely studied disease that might be caused by rapidly increased right ventricle (RV) afterload during acute pulmonary embolism, hypoxic pulmonary vasoconstriction, or after cardiac transplantation or prolonged cardiopulmonary bypass. In these conditions, acute RHF is a major cause of morbidity and mortality. The protein kinase B, known as Akt, signaling pathway is a factor in cardiac hypertrophy, remodeling, and cardiomyocyte proliferation in the left ventricle (LV) [2, 3]. Few studies have been conducted on Akt signaling in the right heart. In PAB-induced acute RHF, the effects of Akt signaling are still unknown
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