title: Ca²⁺ signal-induced cardiomyocyte hypertrophy through activation of myocardin.
abstract: Hypertrophic growth of cardiomyocytes in response to pressure overload is an important stage during the development of many cardiac diseases. Ca(2+) overload as well as subsequent activation of Ca(2+) signaling pathways has been reported to induce cardiac hypertrophy. Myocardin, a transcription cofactor of serum response factor (SRF), is a key transducer of hypertrophic signals. However, the direct role of myocardin in Ca(2+) signal-induced cardiomyocyte hypertrophy has not been explained clearly. In the present study, we discovered that embryonic rat heart-derived H9c2 cells responded to the stimulation of calcium ionophore A23187 with a cell surface area enlargement and an increased expression of cardiac hypertrophy marker genes. Increased Ca(2+) also induces an organization of sarcomeres in neonatal rat cardiomyocytes, as revealed by α-actinin staining. Increased Ca(2+) could upregulate the expression of myocardin. Knockdown of myocardin by shRNA attenuates hypertrophic responses triggered by increased intracellular Ca(2+), suggesting that Ca(2+) signals induce cardiomyocyte hypertrophy partly through activation of myocardin. Furthermore, A23187 treatment directly activates myocardin promoter, chelation of Ca(2+) by EGTA inhibits this activation and knockdown of myocardin expression using shRNA also abrogates A23187-induced ANF and SK-α-actin promoter activity. CSA (calcineurin inhibitor) and KN93 (CaMKII inhibitor) inhibit A23187-induced the increase in myocardin expression. These results suggest that myocardin plays a critical role in Ca(2+) signal-induced cardiomyocyte hypertrophy, which may serve as a novel mechanism that is important for cardiac hypertrophy.
authors.affiliation: Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, 300457, PR China.
authors.forename: Man
authors.initials: M
authors.lastname: Li
authors.affiliation: Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, 300457, PR China. Electronic address: wn929@tust.edu.cn.
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.affiliation: Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, 300457, PR China.
authors.forename: Hui-Qin
authors.initials: HQ
authors.lastname: Gong
authors.affiliation: Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, 300457, PR China.
authors.forename: Wei-Zong
authors.initials: WZ
authors.lastname: Li
authors.affiliation: Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, 300457, PR China; Institute of Biology and Medicine, Wuhan University of Science and Technology, 430000, PR China.
authors.forename: Xing-Hua
authors.initials: XH
authors.lastname: Liao
authors.affiliation: Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, 300457, PR China.
authors.forename: Xiao-Long
authors.initials: XL
authors.lastname: Yang
authors.affiliation: Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, 300457, PR China.
authors.forename: Hong-Peng
authors.initials: HP
authors.lastname: He
authors.affiliation: Institute of Biology and Medicine, Wuhan University of Science and Technology, 430000, PR China.
authors.forename: Dong-Sun
authors.initials: DS
authors.lastname: Cao
authors.affiliation: Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, 300457, PR China; Institute of Biology and Medicine, Wuhan University of Science and Technology, 430000, PR China.. Electronic address: tony@tust.edu.cn.
authors.forename: Tong-Cun
authors.initials: TC
authors.lastname: Zhang
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D000001:Calcimycin / Q000494:pharmacology; D065095:Calcineurin Inhibitors / Q000494:pharmacology; D002118:Calcium / Q000737:chemistry / Q000494:pharmacology; D065096:Calcium Chelating Agents / Q000494:pharmacology; D061207:Calcium Ionophores / Q000494:pharmacology; D020013:Calcium Signaling / Q000235:genetics*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors; D006332:Cardiomegaly / Q000235:genetics / Q000473:pathology*; D002460:Cell Line; D004533:Egtazic Acid / Q000494:pharmacology; D004789:Enzyme Activation; D032383:Myocytes, Cardiac / Q000473:pathology*; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D012518:Sarcomeres; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D000099251:Myocardin
chemical_list: D000199:Actins; D009320:Atrial Natriuretic Factor; D000001:Calcimycin; D065095:Calcineurin Inhibitors; D002118:Calcium; D065096:Calcium Chelating Agents; D061207:Calcium Ionophores; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D004533:Egtazic Acid; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D015534:Trans-Activators; D000099251:Myocardin
keywords: Ca(2+) signals; Cardiomyocyte hypertrophy; Myocardin