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.
Highlights
Pulmonary arterial hypertension (PAH) is a disease characterized by pulmonary vascular remodeling and increased pulmonary vascular resistance, culminating in right ventricular (RV) hypertrophy and failure [1]
We determined the effect of p53 activation by Quinacrine on right ventricular remodeling and function in a pulmonary artery banding (PAB) model of RV hypertrophy one week after the surgery, the time point, at which p53 levels were negligibly different to SHAM-operated controls
Quinacrine treatment at the compensated stage of RVH resulted in a strong p53 accumulation with activation of its downstream signaling, both RV hypertrophy and RV function have not been significantly impaired
Summary
Pulmonary arterial hypertension (PAH) is a disease characterized by pulmonary vascular remodeling and increased pulmonary vascular resistance, culminating in right ventricular (RV) hypertrophy and failure [1]. RV failure follows a period of compensation, so called adaptive hypertrophy, which is characterized by maintained myocardial vascularization. The transition to maladaptive RV hypertrophy is associated with a decrease in vascularization [2]. In various experimental models of PH associated with RV failure, reduced myocardial vascular density has been proposed to be a critical contributor to the transition from adaptive to maladaptive RV hypertrophy [3,4,5,6,7]. In left ventricular hypertrophy (LVH) model, induced by transaortic constriction (TAC), proper cardiac angiogenesis is controlled by the hypoxia-inducible factor-1 (HIF-1α) contributing to adaptive LVH. In the pressure-overload induced LVH, p53 has been demonstrated to contribute to maladaptive myocardial remodeling via inhibition of HIF-1α activity and impairment of cardiac angiogenesis [8]. RVs from maladaptive RV hypertrophy of Monocrotaline (MCT)-induced PAH exhibit elevations in p53 levels, no changes on RV CM apoptosis have been noted [13]
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