Circulation Research. 2004;94:514-524
Published online before print January 15, 2004, doi: 10.1161/01.RES.0000117306.10142.50
Published online before print January 15, 2004, doi: 10.1161/01.RES.0000117306.10142.50
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© 2004 American Heart Association, Inc.
Integrative Physiology |
Cardiac Stem Cell and Myocyte Aging, Heart Failure, and Insulin-Like Growth Factor-1 Overexpression
From the Cardiovascular Research Institute (D.T., M.R., D.N., E.M., A.M., E.Z., K.U., B.N.-G., J.K., P.A., A.L.), New York Medical College, Valhalla, NY; Cardiology Division (A.R.), Massachusetts General Hospital, Harvard Medical School, Boston, Mass; Molecular Cardiology (K.W.), Boston University, Boston, Mass; SDSU Heart Institute and Department of Biology (I.S., M.A.S.), San Diego State University, San Diego, Calif.
Correspondence to Annarosa Leri, MD, Cardiovascular Research Institute, Department of Medicine, Vosburgh Pavilion, Room 318, New York Medical College, Valhalla, NY 10595. E-mail annarosa_leri{at}nymc.edu
To determine whether cellular aging leads to a cardiomyopathy and heart failure, markers of cellular senescence, cell death, telomerase activity, telomere integrity, and cell regeneration were measured in myocytes of aging wild-type mice (WT). These parameters were similarly studied in insulin-like growth factor-1 (IGF-1) transgenic mice (TG) because IGF-1 promotes cell growth and survival and may delay cellular aging. Importantly, the consequences of aging on cardiac stem cell (CSC) growth and senescence were evaluated. Gene products implicated in growth arrest and senescence, such as p27Kip1, p53, p16INK4a, and p19ARF, were detected in myocytes of young WT mice, and their expression increased with age. IGF-1 attenuated the levels of these proteins at all ages. Telomerase activity decreased in aging WT myocytes but increased in TG, paralleling the changes in Akt phosphorylation. Reduction in nuclear phospho-Akt and telomerase resulted in telomere shortening and uncapping in WT myocytes. Senescence and death of CSCs increased with age in WT impairing the growth and turnover of cells in the heart. DNA damage and myocyte death exceeded cell formation in old WT, leading to a decreased number of myocytes and heart failure. This did not occur in TG in which CSC-mediated myocyte regeneration compensated for the extent of cell death preventing ventricular dysfunction. IGF-1 enhanced nuclear phospho-Akt and telomerase delaying cellular aging and death. The differential response of TG mice to chronological age may result from preservation of functional CSCs undergoing myocyte commitment. In conclusion, senescence of CSCs and myocytes conditions the development of an aging myopathy.
Key Words: telomerase • telomere dysfunction • cellular senescence
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