title: ROCK1/p53/NOXA signaling mediates cardiomyocyte apoptosis in response to high glucose in vitro and vivo.
abstract: Gestational diabetes mellitus is a risk factor for congenital heart defects; however, the molecular basis of the congenital heart anomalies remains obscure. Previous reports showed a positive correlation between abnormal cardiomyocyte apoptosis and ventricular wall thinness, one type of congenital heart anomaly. This work explored the expression pattern and molecular mechanism of the Rho-associated coiled-coil containing protein kinase 1 (ROCK1) gene in cardiomyocyte apoptosis and genesis of ventricular wall thinness. In this report, we found a marked increase in the number of apoptotic cardiomyocytes in response to high glucose (HG) treatment. Moreover, up-regulation of ROCK1 expression observed in diabetic offspring compared with controls was potentially associated with cardiomyocyte apoptosis and the ventricular wall thinness. Further investigation showed that p53 and NOXA protein levels increased during ROCK1-meidated apoptosis in response to HG. In response to HG, whereby ROCK1 phosphorylated p53 at Ser15 to up-regulate its protein level. Furthermore, we found that p53 mediated the expression of NOXA during HG-induced apoptosis, and histone acetyltransferase p300 participated in this process. These findings reveal a novel regulatory mechanism of ROCK1/p53/NOXA signaling in modulating cardiomyocyte apoptosis in vitro and maternal diabetes-induced congenital heart defects in vivo.
authors.affiliation: Department of Genetics, National Research Institute for Family Planning, Health Department, Beijing, China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Su
authors.affiliation: Department of Genetics, National Research Institute for Family Planning, Health Department, Beijing, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Guan
authors.affiliation: Linyi Academy of Technology Cooperation and Application, Linyi, Shandong Province, China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Department of Genetics, National Research Institute for Family Planning, Health Department, Beijing, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Genetics, National Research Institute for Family Planning, Health Department, Beijing, China.
authors.forename: Cuige
authors.initials: C
authors.lastname: Shi
authors.affiliation: Department of Genetics, National Research Institute for Family Planning, Health Department, Beijing, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Fang Cheng Gang Senior Middle School, Guangxi Zhuang Autonomous, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Genetics, National Research Institute for Family Planning, Health Department, Beijing, China.
authors.forename: Cailing
authors.initials: C
authors.lastname: Lu
authors.affiliation: Department of Genetics, National Research Institute for Family Planning, Health Department, Beijing, China. Electronic address: jswkysgc@126.com.
authors.forename: Xu
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450007, China. Electronic address: zhaojingheart@126.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D005260:Female; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D006330:Heart Defects, Congenital / Q000378:metabolism / Q000473:pathology; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D011254:Pregnancy in Diabetics / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*; D015854:Up-Regulation / Q000187:drug effects*; D054460:rho-Associated Kinases / Q000096:biosynthesis*
chemical_list: C539472:Pmaip1 protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; C578418:ROCK1 protein, rat; D054460:rho-Associated Kinases; D005947:Glucose
keywords: Congenital heart defects; Gestational diabetes mellitus; NOXA; ROCK1; p300; p53