The DNA damage response (DDR) plays a pivotal role in maintaining genome integrity. DNA damage and DDR activation are observed in the failing heart, however, the type of DNA damage and its role in the pathogenesis of heart failure remain elusive. Here we show the critical role of DNA single-strand break (SSB) in the pathogenesis of pressure overload-induced heart failure. Accumulation of unrepaired SSB is observed in cardiomyocytes of the failing heart. Unrepaired SSB activates DDR and increases the expression of inflammatory cytokines through NF-κB signalling. Pressure overload-induced heart failure is more severe in the mice lacking XRCC1, an essential protein for SSB repair, which is rescued by blocking DDR activation through genetic deletion of ATM, suggesting the causative role of SSB accumulation and DDR activation in the pathogenesis of heart failure. Prevention of SSB accumulation or persistent DDR activation may become a new therapeutic strategy against heart failure.

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SummaryDuchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene which encodes dystrophin protein.Dystrophin defect affects cardiac muscle as well as skeletal muscle. Cardiac dysfunction is observed in all patients with DMD over 18 years of age, but there is no curative treatment for DMD cardiomyopathy. To establish novel experimental platforms which reproduce the cardiac phenotype of DMD patients, here we established iPS cell lines from T lymphocytes donated from two DMD patients, with a protocol using Sendai virus vectors. We successfully conducted the differentiation of the DMD patient-specific iPS cells into beating cardiomyocytes. DMD patient-specific iPS cells and iPS cell-derived cardiomyocytes would be a useful in vitro experimental system with which to investigate DMD cardiomyopathy. ( DMD is caused by mutations in the DMD gene which encodes dystrophin protein. Dystrophin protein constitutes a core element of dystrophin-glycoprotein complex, and plays essential roles in transmitting force and maintaining sarcolemma stability. Lack of dystrophin protein impairs membrane integrity and causes progressive degeneration and loss of skeletal muscle. Dystrophin defect also affects cardiac muscle and cardiac dysfunction is observed in all patients with DMD over 18 years of age.2) With recent advances in the management of respiratory failure for patients with DMD, increasing attention has been paid to cardiac dysfunction since the heart failure is becoming the most frequent cause of death among adult DMD patients.3) Although medical treatments using betablockers and angiotensin converting enzyme inhibitors have been reported to delay progression of DMD cardiomyopathy, 4-6) the effects are limited. Exon skipping has been developed as a novel gene therapy for DMD and some effects have been observed in skeletal muscles, however, the recovery of dystrophin was only scarcely observed in heart muscle due to the difficulty of delivering antisense oligonucleotides to cardiomyocytes.7) Thus, we need to clarify the underlying mechanisms of DMD-associated cardiomyopathy and develop novel therapeutic strategies.To date, mdx mice have been widely used as an animal model of dystrophin gene abnormality. Recent studies have reported various abnormalities in cardiomyocytes of mdx mice such as increased susceptibility to stretch-mediated calcium overload, 8) abnormal activation in stretch-activated channels, 9) diastolic calcium leak from sarcoplasmic reticulum, 10,11) and hyperactivation of X-ROS signaling.12) Nevertheless, mdx mice have critical limitations as a model for DMD cardiomyopathy since they do not develop heart failure. 13,14) On the other hand, using both in vitro and in vivo non-genetic rat models, a recent study demonstrated that microRNA-340-5p may be involved in the progression of heart failure through the interaction with DMD gene.15) Considering these issues, novel experimental platforms that reproduce the cardiac phenotype of DMD patients is critically required for the development of new drugs a...

Cardiac fibrosis plays an important role in cardiac remodeling after myocardial infarction (MI). The molecular mechanisms that promote cardiac fibrosis after MI are well studied; however, the mechanisms by which the progression of cardiac fibrosis becomes attenuated after MI remain poorly understood. Recent reports show the role of cellular senescence in limiting tissue fibrosis. In the present study, we tested whether cellular senescence of cardiac fibroblasts (CFs) plays a role in attenuating the progression of cardiac fibrosis after MI. We found that the number of γH2AX-positive CFs increased up to day 7, whereas the number of proliferating CFs peaked at day 4 after MI. Senescent CFs were also observed at day 7, suggesting that attenuation of CF proliferation occurred simultaneously with the activation of the DNA damage response (DDR) system and the appearance of senescent CFs. We next cultured senescent CFs with non-senescent CFs and showed that senescent CFs suppressed proliferation of the surrounding non-senescent CFs in a juxtacrine manner. We also found that the blockade of DDR by Atm gene deletion sustained the proliferation of CFs and exacerbated the cardiac fibrosis at the early stage after MI. Our results indicate the role of DDR activation and cellular senescence in limiting cardiac fibrosis after MI. Regulation of cellular senescence in CFs may become one of the therapeutic strategies for preventing cardiac remodeling after MI.