1. Effect of p53 activation on experimental right ventricular hypertrophy
- Author
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Veeroju, Swathi, Mamazhakypov, Argen, Rai, Nabham, Kojonazarov, Baktybek, Nadeau, Valerie, Breuils-Bonnet, Sandra, Li, Ling, Weissmann, Norbert, Rohrbach, Susanne, Provencher, Steve, Bonnet, Sébastien, Seeger, Werner, Schermuly, Ralph, and Novoyatleva, Tatyana
- Subjects
Male ,Apoptosis ,Biochemistry ,Epithelium ,Mitochondria, Heart ,Mice ,Animal Cells ,Medicine and Health Sciences ,Myocytes, Cardiac ,Pulmonary Arteries ,Energy-Producing Organelles ,Cells, Cultured ,Cardiomyocytes ,Cell Death ,Fatty Acids ,Heart ,Arteries ,Animal Models ,Middle Aged ,Mitochondria ,Experimental Organism Systems ,Cell Processes ,Quinacrine ,Medicine ,Female ,Cellular Types ,Anatomy ,Cellular Structures and Organelles ,Research Article ,Adult ,Sarcomeres ,Science ,Muscle Tissue ,Mouse Models ,Bioenergetics ,Research and Analysis Methods ,Model Organisms ,Animals ,Humans ,Aged ,Muscle Cells ,Hypertrophy, Right Ventricular ,Biology and Life Sciences ,Endothelial Cells ,Proteins ,Epithelial Cells ,Cell Biology ,Fibroblasts ,Mice, Inbred C57BL ,Biological Tissue ,Cardiovascular Anatomy ,Animal Studies ,Blood Vessels ,Tumor Suppressor Protein p53 ,Collagens ,Heme Oxygenase-1 - 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.
- Published
- 2020