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Effect of p53 activation on experimental right ventricular hypertrophy.

ABSTRACT: The leading cause of death in Pulmonary Arterial Hypertension (PAH) is right ventricular (RV) failure. The tumor suppressor p53 has been associated with left ventricular hypertrophy (LVH) and remodeling but its role in RV hypertrophy (RVH) is unclear. The purpose of this study was to determine whether pharmacological activation of p53 by Quinacrine affects RV remodeling and function in the pulmonary artery banding (PAB) model of compensated RVH in mice. The effects of p53 activation on cellular functions were studied in isolated cardiomyocytes, cardiac fibroblasts and endothelial cells (ECs). The expression of p53 was examined both on human RV tissues from patients with compensated and decompensated RVH and in mouse RV tissues early and late after the PAB. As compared to control human RVs, there was no change in p53 expression in compensated RVH, while a marked upregulation was found in decompensated RVH. Similarly, in comparison to SHAM-operated mice, unaltered RV p53 expression 7 days after PAB, was markedly induced 21 days after the PAB. Quinacrine induced p53 accumulation did not further deteriorate RV function at day 7 after PAB. Quinacrine administration did not increase EC death, neither diminished EC number and capillary density in RV tissues. No major impact on the expression of markers of sarcomere organization, fatty acid and mitochondrial metabolism and respiration was noted in Quinacrine-treated PAB mice. p53 accumulation modulated the expression of Heme Oxygenase 1 (HO-1) and Glucose Transporter (Glut1) in mouse RVs and in adult cardiomyocytes. We conclude that early p53 activation in PAB-induced RVH does not cause substantial detrimental effects on right ventricular remodeling and function.

SUBMITTER: Veeroju S

PROVIDER: S-EPMC7304610 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Effect of p53 activation on experimental right ventricular hypertrophy.

Veeroju Swathi S Mamazhakypov Argen A Rai Nabham N Kojonazarov Baktybek B Nadeau Valerie V Breuils-Bonnet Sandra S Li Ling L Weissmann Norbert N Rohrbach Susanne S Provencher Steve S Bonnet Sébastien S Seeger Werner W Schermuly Ralph R Novoyatleva Tatyana T

PloS one 20200619 6

The leading cause of death in Pulmonary Arterial Hypertension (PAH) is right ventricular (RV) failure. The tumor suppressor p53 has been associated with left ventricular hypertrophy (LVH) and remodeling but its role in RV hypertrophy (RVH) is unclear. The purpose of this study was to determine whether pharmacological activation of p53 by Quinacrine affects RV remodeling and function in the pulmonary artery banding (PAB) model of compensated RVH in mice. The effects of p53 activation on cellular ...[more]

PMID: 32559203

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Project description:Right ventricular hypertrophy (RVH) and RV failure are major determinants of prognosis in pulmonary hypertension and congenital heart disease. In RVH, there is a metabolic shift from glucose oxidation (GO) to glycolysis. Directly increasing GO improves RV function, demonstrating the susceptibility of RVH to metabolic intervention. However, the effects of RVH on fatty acid oxidation (FAO), the main energy source in adult myocardium, are unknown. We hypothesized that partial inhibitors of FAO (pFOXi) would indirectly increase GO and improve RV function by exploiting the reciprocal relationship between FAO and GO (Randle's cycle). RVH was induced in adult Sprague-Dawley rats by pulmonary artery banding (PAB). pFOXi were administered orally to prevent (trimetazidine, 0.7 g/L for 8 weeks) or regress (ranolazine 20 mg/day or trimetazidine for 1 week, beginning 3 weeks post-PAB) RVH. Metabolic, hemodynamic, molecular, electrophysiologic, and functional comparisons with sham rats were performed 4 or 8 weeks post-PAB. Metabolism was quantified in RV working hearts, using a dual-isotope technique, and in isolated RV myocytes, using a Seahorse Analyzer. PAB-induced RVH did not cause death but reduced cardiac output and treadmill walking distance and elevated plasma epinephrine levels. Increased RV FAO in PAB was accompanied by increased carnitine palmitoyltransferase expression; conversely, GO and pyruvate dehydrogenase (PDH) activity were decreased. pFOXi decreased FAO and restored PDH activity and GO in PAB, thereby increasing ATP levels. pFOXi reduced the elevated RV glycogen levels in RVH. Trimetazidine and ranolazine increased cardiac output and exercise capacity and attenuated exertional lactic acidemia in PAB. RV monophasic action potential duration and QTc interval prolongation in RVH normalized with trimetazidine. pFOXi also decreased the mild RV fibrosis seen in PAB. Maladaptive increases in FAO reduce RV function in PAB-induced RVH. pFOXi inhibit FAO, which increases GO and enhances RV function. Trimetazidine and ranolazine have therapeutic potential in RVH.

Project description:Development of right ventricular (RV) hypertension eventually contributes to RV and left ventricular (LV) myocardial fibrosis and dysfunction. The molecular mechanisms are not fully elucidated.Pulmonary artery banding was used to induce RV hypertension in rats in vivo. Then, we evaluated cardiac function and regional remodeling 6 weeks after pulmonary artery banding. To further elucidate mechanisms responsible for regional cardiac remodeling, we also mimicked RV hypertensive stress by cyclic mechanical stretching applied to confluent cultures of cardiac fibroblasts, isolated from the RV free wall, septal hinge points, and LV free wall. Echocardiography and catheter evaluation demonstrated that rats in the pulmonary artery banding group developed RV hypertension with leftward septal displacement, LV compression, and increased LV end-diastolic pressures. Picrosirius red staining indicated that pulmonary artery banding induced marked RV fibrosis and dysfunction, with prominent fibrosis and elastin deposition at the septal hinge points but less LV fibrosis. These changes were associated with proportionally increased expressions of integrin-?1 and profibrotic signaling proteins, including phosphorylated Smad2/3 and transforming growth factor-?1. Moreover, mechanically stretched fibroblasts also expressed significantly increased levels of ?-smooth muscle actin, integrin-?1, transforming growth factor-?1, collagen I deposition, and wrinkle formation on gel assays, consistent with myofibroblast transformation. These changes were not observed in parallel cultures of mechanically stretched fibroblasts, preincubated with the integrin inhibitor (BTT-3033).Experimentally induced RV hypertension triggers regional RV, hinge-point, and LV integrin ?1-dependent mechanotransduction signaling pathways that eventually trigger myocardial fibrosis via transforming growth factor-?1 signaling. Reduced LV fibrosis and preserved global function, despite geometrical and pressure aberrations, suggest a possible elastin-mediated protective mechanism at the septal hinge points.

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Effect of p53 activation on experimental right ventricular hypertrophy.

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Effect of p53 activation on experimental right ventricular hypertrophy.

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