Telomere attrition and Chk2 activation in human heart failure.
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 repeat- binding 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.
Oh
Hidemasa
H
Center for Cardiovascular Development, and Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Wang
Sam C
SC
Prahash
Arun
A
Sano
Motoaki
M
Moravec
Christine S
CS
Taffet
George E
GE
Michael
Lloyd H
LH
Youker
Keith A
KA
Entman
Mark L
ML
Schneider
Michael D
MD
D000818:Animals; D001483:Base Sequence; D002303:Cardiac Output, Low / Q000235:genetics*; D064447:Checkpoint Kinase 2; D017931:DNA Primers; D006801:Humans; D051379:Mice; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D051381:Rats; D017207:Rats, Sprague-Dawley; D016615:Telomere
D017931:DNA Primers; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; C578633:Chek2 protein, mouse; C578632:Chek2 protein, rat; D017346:Protein Serine-Threonine Kinases