Telomere attrition and Chk2 activation in human heart failure

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.

Oxidative stress induces senescence in chondrocytes

“…Accordingly, over-expression of TRF2 showed protective effects in terms of oxidative stress induced apoptosis. 36 On the other hand, chondrocytes and other somatic cells 37 were shown to enter a senescent state in spite of abundant TRF expression. Oxidant insult causes DNA base alterations and thus changes telomere sequences.…”

Telomere attrition predominantly occurs in precursor lesions during in vivo carcinogenic process of the uterine cervix

“…Chk2 is involved in the DNA damage signal transduction pathway between ATM and p53, and is phosphorylated/activated by ATM upon DNA damage or threshold levels of telomeres (DiTullio et al, 2002;Fagagna Fd et al, 2003;Oh et al, 2003). The widespread Chk2 activation observed in cervical carcinomas represents the presence of DNA damage and genetic instability (DiTullio et al, 2002).…”

“…In vitro studies of human cultured cells indicate that critically shortened telomeres mimic double-stranded DNA breaks (DSBs), thereby activating the DNA damage response through the ATM-p53 pathway (Karlseder et al, 1999;Pandita, 2002). Since Chk2 is an essential mediator between ATM and p53, and its activation occurs upon telomere shortening in senescent human fibroblasts and heart failure (DiTullio et al, 2002;Fagagna Fd et al, 2003;Oh et al, 2003), we thus sought to determine whether and how the DNA checkpoint responded to telomere erosions in precursor and malignant lesions by assessing the phosphorylated Chk2 at Thr68. There was no detectable phosphoryla- tion of Chk2 protein in normal areas of all the samples, whereas a positive staining was seen in 11/20 of CINs and 9/10 of invasive cancers, respectively, which suggests a constitutive activation of the DNA damage response pathway.…”

Activation of Rho-associated coiled-coil protein kinase 1 (ROCK-1) by caspase-3 cleavage plays an essential role in cardiac myocyte apoptosis

“…To substantiate the role of ROCK-1 in this proteolytic cascade process in vivo, ROCK-1-null mice, which are viable (15), were subjected to severe pressure overload as a pathophysiological signal for apoptosis (15,20). Consistent with the siRNA results, we found that ROCK-1 Ϫ/Ϫ mice exhibited significantly reduced TUNEL-positive cardiac myocytes (46 myocytes per 10 5 nuclei) compared with WT mice (93 myocytes per 10 5 nuclei, P Ͻ 0.05) when subjected to pressure overload through aortic banding for D and E).…”