Telomere attrition and Chk2 activation in human heart failure

Hidemasa Oh, Sam C. Wang, Arun Prahash, Motoaki Sano, Christine S. Moravec, George E. Taffet, Lloyd H. Michael, Keith A. Youker, Mark L. Entman, Michael D. Schneider

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Abstract

The "postmitotic" phenotype in adult cardiac muscle exhibits similarities to replicative senescence more generally and constitutes a barrier to effective restorative growth in heart disease. Telomere dysfunction is implicated in senescence and apoptotic signaling but its potential role in heart disorders is unknown. Here, we report that cardiac apoptosis in human heart failure is associated specifically with defective expression of the telomere repeatbinding factor TRF2, telomere shortening, and activation of the DNA damage checkpoint kinase, Chk2. In cultured cardiomyocytes, interference with either TRF2 function or expression triggered telomere erosion and apoptosis, indicating that cell death can occur via this pathway even in postmitotic, noncycling cells; conversely, exogenous TRF2 conferred protection from oxidative stress. In vivo, mechanical stress was sufficient to down-regulate TRF2, shorten telomeres, and activate Chk2 in mouse myocardium, and transgenic expression of telomerase reverse transcriptase conferred protection from all three responses. Together, these data suggest that apoptosis in chronic heart failure is mediated in part by telomere dysfunction and suggest an essential role for TRF2 even in postmitotic cells.

Original languageEnglish (US)
Pages (from-to)5378-5383
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number9
DOIs
StatePublished - Apr 29 2003

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Telomere
Heart Failure
Telomere Shortening
Apoptosis
Myocardium
Mechanical Stress
Cell Aging
Telomerase
Cardiac Myocytes
Transgenic Mice
DNA Damage
Heart Diseases
Oxidative Stress
Cell Death
Phosphotransferases
Down-Regulation
Phenotype
Growth

ASJC Scopus subject areas

  • General

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Telomere attrition and Chk2 activation in human heart failure. / Oh, Hidemasa; Wang, Sam C.; Prahash, Arun; Sano, Motoaki; Moravec, Christine S.; Taffet, George E.; Michael, Lloyd H.; Youker, Keith A.; Entman, Mark L.; Schneider, Michael D.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 9, 29.04.2003, p. 5378-5383.

Research output: Contribution to journalArticle

Oh, H, Wang, SC, Prahash, A, Sano, M, Moravec, CS, Taffet, GE, Michael, LH, Youker, KA, Entman, ML & Schneider, MD 2003, 'Telomere attrition and Chk2 activation in human heart failure', Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 9, pp. 5378-5383. https://doi.org/10.1073/pnas.0836098100
Oh, Hidemasa ; Wang, Sam C. ; Prahash, Arun ; Sano, Motoaki ; Moravec, Christine S. ; Taffet, George E. ; Michael, Lloyd H. ; Youker, Keith A. ; Entman, Mark L. ; Schneider, Michael D. / Telomere attrition and Chk2 activation in human heart failure. In: Proceedings of the National Academy of Sciences of the United States of America. 2003 ; Vol. 100, No. 9. pp. 5378-5383.
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