The objective of this application is to demonstrate that the heart belongs to the group of self-renewing organs. The myocardium is postulated to contain a subgroup of cardiomyocytes which regulate cardiac growth: unipotent myocyte stem cells and amplifying cells. Unipotent myocyte stem cells are characterized by the presence of telomerase, while this enzyme is absent in amplifying cells. Amplifying cells, which derive from stem cells, replicate rapidly but undergo progressive telomeric shortening and accumulation of specialized structures, reaching growth arrest and terminal differentiation. Telomerase activity restores telomeric length during stem cell division, although the function of this enzyme decreases with age leading to erosion of telomeres and apoptotic cell death in the old heart. IGF-1, c-myc, and Bcl-2 enhance telomerase activity possibly increasing the stem cell number and their lifespan. IGF-1 and Bcl-2 further expand the stem pool size by exerting antiapoptotic effects. Conversely, the transcription factor p53 and p53 dependent genes, such as Bax and angiotensin (Aogen), have opposite consequences on myocyte growth. The tumor suppressor decreases telomerase activity and is activated by Ang II, whose synthesis is stimulated by p53-induced transcription of Aogen. The negative influence of p53 on telomerase and cell growth is also promoted via up regulation of the cdk inhibitorp21 and the proapoptotic gene product Bax. The oncoprotein p19ARF increases p53 stability and quantity by sequestering Mdm2 at the nucleolar level. Mdm2 is a p53-inducible gene that has a negative feedback on p53 by generating inactive Mdm2-p53 complexes. IGF-1 leads to transcription of Mdm2 in myocytes and, thereby, attenuates the impact of p53 and AngII on telomerase activity. P16INK4 favors p53-mediated responses by increasing the half-life of p21. Additionally, p16INK4 maintains RB in its hypophosphorylated form affecting telomerase activity and cell growth. These multiple modulators of telomerase activity and stem cell function will be analyzed from late fetal development to senescence in transgenic mice overexpressing IGF-1 in myocytes. Both genders will be studed as a function of age and under extreme conditions of accelerated growth produced by myocardial infarction, since female myocytes possess higher level of expression of IGF-1 and improved resistance to apoptotic death. Female mice are expected to have a larger number of telomerase competent cells and greater potential or myocyte growth under physiologic and pathologic stimuli.
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