title: Novel role for caspase-activated DNase in the regulation of pathological cardiac hypertrophy.
abstract: Caspase-activated DNase (CAD) is a double-strand-specific endonuclease that is responsible for the cleavage of nucleosomal spacer regions and subsequent chromatin condensation during apoptosis. Given that several endonucleases (eg, DNase I, DNase II, and Endog) have been shown to regulate pathological cardiac hypertrophy, we questioned whether CAD, which is critical for the induction of DNA fragmentation, plays a pivotal role in pressure overload-elicited cardiac hypertrophy. A CAD-knockout mouse model was generated and subjected to aortic banding for 8 weeks. The extent of cardiac hypertrophy was evaluated by echocardiography and pathological and molecular analyses. Our results demonstrated that the disruption of CAD attenuated pressure overload-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction. Conversely, transgenic mice with cardiac-specific overexpression of CAD showed an aggravated cardiac hypertrophic response to chronic pressure overload. Mechanistically, we discovered that the expression and activation of mitogen-activated protein kinase-extracellular signal-regulated kinase 1/2 was significantly reduced in the CAD-knockout hearts compared with the control hearts; however, they were greatly increased in the CAD-overexpressing hearts after aortic banding. Similar results were observed in ex vivo cultured neonatal rat cardiomyocytes after treatment with angiotensin II for 48 hours. These data indicate that CAD functions as a necessary modulator of the hypertrophic response by regulating the mitogen-activated protein kinase-extracellular signal-regulated kinase 1/2 signaling pathway in the heart. Our study suggests that CAD might be a novel target for the treatment of pathological cardiac hypertrophy and heart failure.
authors: From the Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (L.G., Kun Huang, D.H., Kai Huang); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., X.L., H.L.); Cardiovascular Research Institute, Wuhan University, Wuhan, China (D.-S.J., X.L., H.L.); and Department of Cell Biology, College of Life Sciences, Wuhan University, Wuhan, China (X.-D.Z.).
authors: Lu
authors: L
authors: Gao
authors: From the Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (L.G., Kun Huang, D.H., Kai Huang); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., X.L., H.L.); Cardiovascular Research Institute, Wuhan University, Wuhan, China (D.-S.J., X.L., H.L.); and Department of Cell Biology, College of Life Sciences, Wuhan University, Wuhan, China (X.-D.Z.).
authors: Kun
authors: K
authors: Huang
authors: From the Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (L.G., Kun Huang, D.H., Kai Huang); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., X.L., H.L.); Cardiovascular Research Institute, Wuhan University, Wuhan, China (D.-S.J., X.L., H.L.); and Department of Cell Biology, College of Life Sciences, Wuhan University, Wuhan, China (X.-D.Z.).
authors: Ding-Sheng
authors: DS
authors: Jiang
authors: From the Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (L.G., Kun Huang, D.H., Kai Huang); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., X.L., H.L.); Cardiovascular Research Institute, Wuhan University, Wuhan, China (D.-S.J., X.L., H.L.); and Department of Cell Biology, College of Life Sciences, Wuhan University, Wuhan, China (X.-D.Z.).
authors: Xiaoxiong
authors: X
authors: Liu
authors: From the Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (L.G., Kun Huang, D.H., Kai Huang); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., X.L., H.L.); Cardiovascular Research Institute, Wuhan University, Wuhan, China (D.-S.J., X.L., H.L.); and Department of Cell Biology, College of Life Sciences, Wuhan University, Wuhan, China (X.-D.Z.).
authors: Dan
authors: D
authors: Huang
authors: From the Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (L.G., Kun Huang, D.H., Kai Huang); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., X.L., H.L.); Cardiovascular Research Institute, Wuhan University, Wuhan, China (D.-S.J., X.L., H.L.); and Department of Cell Biology, College of Life Sciences, Wuhan University, Wuhan, China (X.-D.Z.).
authors: Hongliang
authors: H
authors: Li
authors: From the Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (L.G., Kun Huang, D.H., Kai Huang); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., X.L., H.L.); Cardiovascular Research Institute, Wuhan University, Wuhan, China (D.-S.J., X.L., H.L.); and Department of Cell Biology, College of Life Sciences, Wuhan University, Wuhan, China (X.-D.Z.).
authors: Xiao-Dong
authors: XD
authors: Zhang
authors: From the Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (L.G., Kun Huang, D.H., Kai Huang); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., X.L., H.L.); Cardiovascular Research Institute, Wuhan University, Wuhan, China (D.-S.J., X.L., H.L.); and Department of Cell Biology, College of Life Sciences, Wuhan University, Wuhan, China (X.-D.Z.). huangkai1@hust.edu.cn.
authors: Kai
authors: K
authors: Huang
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D006332:Cardiomegaly / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D003851:Deoxyribonucleases / Q000096:biosynthesis / Q000235:genetics*; D004195:Disease Models, Animal; D004452:Echocardiography; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D012313:RNA / Q000235:genetics*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D016277:Ventricular Function, Left / Q000502:physiology
chemical_list: D012313:RNA; D003851:Deoxyribonucleases; C109663:caspase-activated deoxyribonuclease
keywords: CAD; ERK1/2; MEK1/2; apoptosis; cardiac hypertrophy