Abstract 13125: The Mdm2/p53 Pathway Preserves Normal Adult Heart Function, in vivo
Heart disease is the leading cause of morbidity and mortality worldwide. Adult mammalian cardiomyocytes (CM) exhibit a very limited capacity for proliferation which is insufficient to restore aberrant heart function. When exposed to pressure overload or ischemia, the heart compensates for the increased workload by CM hypertrophy, ultimately leading to maladaptive remodelling. The lack of regenerative cardiomyocyte capacity has immense clinical consequence, therefore, understanding the factors required to induce CM cell division is of great scientific import. The tumor suppressor p53 is a transcription factor which is the most frequent target for mutations in human tumors. p53 protein expression is mainly controlled by the ubiquitin ligase Mdm2, which targets p53 for proteasomal degradation. Low basal p53 activity mediates crucial effects on tumor suppression and growth surveillance in normal tissues. Thus, we investigated whether acute genetic inactivation of the Mdm2/p53 circuitry might regulate cardiac growth and cell cycle re-entry of CM in adult mice, in vivo. Here we show that acute conditional genetic deletion of these two factors in the adult mouse myocardium results in dilated cardiomyopathy and death due to heart failure within ten days. Continuous deficiency of each single factor alone, or heterozygosity for one or both factors favors the development of pathological cardiac hypertrophy. Notably, the acute inactivation of Mdm2/p53, a key pathway controlling replicative potential, is sufficient to induce spontaneous and substantial proliferation of resident cardiomyocytes. Immunofluorescence microscopy of cardiac sections employing CM-specific anti-Mef2a and mitosis-specific anti-phospho-histone H3 (Pi-H3) revealed a dramatically elevated number of Pi-H3 positive CM nuclei in tamoxifen (Tam-)-treated Mdm2f/f;p53f/f;mcm mice (1.08%±0.09; day 8 versus 0.002%±0.002; day 0). Elimination of the two factors induced cytokinesis in 0.08%±0.012 of CM as analyzed by 3D confocal microscopy employing anti-surviving and anti-actinin double immunolabeling. Collectively, our observations provide strong genetic evidence that the Mdm2/p53 pathway is required for the maintenance of normal adult heart function.
- © 2013 by American Heart Association, Inc.