title: Involvement of autophagy in cardiac remodeling in transgenic mice with cardiac specific over-expression of human programmed cell death 5.
abstract: Programmed cell death 5 (PDCD5) is a cytosolic protein suppressing growth of multiple types of cancer cells through activating p53. We hypothesized that PDCD5 plays an essential role in cardiac remodeling and function. PDCD5 was significantly up-regulated in the hearts from mice subjected to angiotensin II treatment or transverse aortic constriction. Thus, we generated transgenic mice over-expressing human PDCD5 under the control of alpha myosin heavy chain promoter to examine the role of PDCD5 in cardiac remodeling. Transgenic founder died spontaneously displayed enlarged heart. The high PDCD5 over-expressing line (10-fold) showed reduced survival rate, increase in heart weight normalized to body weight. Real-Time RT-PCR analysis revealed fetal gene program was up-regulated. Echocardiography and histopathological examination showed characteristics of dilated cardiomyopathy and heart failure in transgenic mice. Western blot and immunohistochemistry analysis showed autophagy was dramatically increased in transgenic mice as compared to WT littermates control mice, while apoptosis remained unchanged. The enhanced autophagy in high over-expressing line was associated with significant increase in p53 activity and its downstream target damage-regulated autophagy modulator expression. The low over-expressing line (3.5-fold) appeared normal, but was more susceptible to angiotensin II-induced cardiac hypertrophy. This study is the first providing evidence that PDCD5 plays an important role in cardiac remodeling.
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Lin
authors.initials: L
authors.lastname: An
authors.forename: Xiwen
authors.initials: X
authors.lastname: Zhao
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.forename: Jianguo
authors.initials: J
authors.lastname: Jia
authors.forename: Yunzeng
authors.initials: Y
authors.lastname: Zou
authors.forename: Xizhi
authors.initials: X
authors.lastname: Guo
authors.forename: Lin
authors.initials: L
authors.lastname: He
authors.forename: Hongxin
authors.initials: H
authors.lastname: Zhu
mesh_terms: D000804:Angiotensin II; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy; D006332:Cardiomegaly / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D002311:Cardiomyopathy, Dilated / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D006333:Heart Failure / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D018995:Myosin Heavy Chains / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D009928:Organ Specificity; D016019:Survival Analysis; D014463:Ultrasonography; D015854:Up-Regulation; D020257:Ventricular Remodeling
chemical_list: D051017:Apoptosis Regulatory Proteins; D009363:Neoplasm Proteins; C117283:PDCD5 protein, human; D000804:Angiotensin II; D018995:Myosin Heavy Chains