title: Expression of mutant p193 and p53 permits cardiomyocyte cell cycle reentry after myocardial infarction in transgenic mice.
abstract: Previous studies have demonstrated that expression of p193 and p53 mutants with dominant-interfering activities renders embryonic stem cell-derived cardiomyocytes responsive to the growth promoting activities of the E1A viral oncoproteins. In this study, the effects of p53 and p193 antagonization on cardiomyocyte cell cycle activity in normal and infarcted hearts were examined. Transgenic mice expressing the p193 and/or the p53 dominant-interfering mutants in the heart were generated. Transgene expression had no effect on cardiomyocyte cell cycle activity in uninjured adult hearts. In contrast expression of either transgene resulted in a marked induction of cardiomyocyte cell cycle activity at the infarct border zone at 4 weeks after permanent coronary artery occlusion. Expression of the p193 dominant-interfering mutant was also associated with an induction of cardiomyocyte DNA synthesis in the interventricular septa of infarcted hearts. A concomitant and marked reduction in hypertrophic cardiomyocyte growth was observed in the septa of hearts expressing the p193 dominant-interfering transgene, suggesting that cell cycle activation might partially counteract the adverse ventricular remodeling that occurs after infarction. Collectively these data suggest that antagonization of p193 and p53 activity relaxes the otherwise stringent regulation of cardiomyocyte cell cycle reentry in the injured adult heart.
authors.affiliation: Wells Center for Pediatric Research and Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, Ind 46202-5225, USA.
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Nakajima
authors.forename: Hisako O
authors.initials: HO
authors.lastname: Nakajima
authors.forename: Shih-Chong
authors.initials: SC
authors.lastname: Tsai
authors.forename: Loren J
authors.initials: LJ
authors.lastname: Field
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D002453:Cell Cycle / Q000235:genetics*; D018389:Codon, Nonsense; D044842:Cullin Proteins; D004261:DNA Replication; D005799:Genes, Dominant; D016158:Genes, p53; D006346:Heart Septum / Q000378:metabolism / Q000473:pathology; D006984:Hypertrophy; D051379:Mice; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000096:biosynthesis / Q000235:genetics; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins; D018389:Codon, Nonsense; C494817:Cul7 protein, mouse; D044842:Cullin Proteins; D009124:Muscle Proteins; D016159:Tumor Suppressor Protein p53