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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL065577-01
Application #
6189935
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
2000-09-01
Project End
2004-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
1
Fiscal Year
2000
Total Cost
$273,875
Indirect Cost
Name
New York Medical College
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Valhalla
State
NY
Country
United States
Zip Code
10595
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Iso, Yoshitaka; Rao, Krithika S; Poole, Charla N et al. (2014) Priming with ligands secreted by human stromal progenitor cells promotes grafts of cardiac stem/progenitor cells after myocardial infarction. Stem Cells 32:674-83
D'Amario, Domenico; Leone, Antonio M; Iaconelli, Antonio et al. (2014) Growth properties of cardiac stem cells are a novel biomarker of patients' outcome after coronary bypass surgery. Circulation 129:157-72
Leri, Annarosa; Rota, Marcello; Hosoda, Toru et al. (2014) Cardiac stem cell niches. Stem Cell Res 13:631-46
Sanada, Fumihiro; Kim, Junghyun; Czarna, Anna et al. (2014) c-Kit-positive cardiac stem cells nested in hypoxic niches are activated by stem cell factor reversing the aging myopathy. Circ Res 114:41-55
Rota, Marcello; Leri, Annarosa; Anversa, Piero (2014) Human heart failure: is cell therapy a valid option? Biochem Pharmacol 88:129-38
Signore, Sergio; Sorrentino, Andrea; Ferreira-Martins, João et al. (2014) Response to letter regarding article ""Inositol 1,4,5-trisphosphate receptors and human left ventricular myocytes"". Circulation 129:e510-1
Anversa, Piero; Leri, Annarosa (2013) Innate regeneration in the aging heart: healing from within. Mayo Clin Proc 88:871-83
Leri, Annarosa; Anversa, Piero (2013) Stem cells and myocardial regeneration: cooperation wins over competition. Circulation 127:165-8
Schoenfeld, Matthew; Frishman, William H; Leri, Annarosa et al. (2013) The existence of myocardial repair: mechanistic insights and enhancements. Cardiol Rev 21:111-20

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