Mechanical cyclic stretch of cardiomyocytes causes cardiac hypertrophy through cardiac-restricted gene expression. Leptin induces cardiomyocyte hypertrophy in response to myocardial stress. In the present study, we evaluated the expression of leptin under cyclic stretch and its role in regulating genetic transcription in cardiomyocytes. Cultured rat neonatal cardiomyocytes were subjected to cyclic stretch, and the expression levels of leptin, ROS (reactive oxygen species) and AngII (angiotensin II) were evaluated. Signal transduction inhibitors were used to identify the pathway of leptin expression. EMSAs were used to identify the binding of leptin/STAT3 (signal transducer and activator of transcription 3) and luciferase assays were used to identify the transcription of leptin in cardiomyocytes. The study also used an in vivo model of AV (aortocaval) shunt in rats to investigate leptin, ROS and AngII expression. Leptin and leptin receptor levels increased after cyclic stretch with the earlier expression of AngII and ROS. Leptin expression was suppressed by AngII receptor blockers, an ROS scavenger [NAC (N-acetylcysteine)], an ERK (extracellular-signal-regulated kinase) pathway inhibitor (PD98059) and ERK siRNA. Binding of leptin/STAT3 was identified by EMSAs, and luciferase assays confirmed the transcription of leptin in neonatal cardiomyocytes after cyclic stretch. Increased MHC (myosin heavy chain) expression and [3H]-proline incorporation in cardiomyocytes was detected after cyclic stretch, which were inhibited by leptin siRNA and NAC. The in vivo model of AV shunt also demonstrated increased levels of plasma and myocardial leptin, ROS and AngII expression after cyclic stretch. Mechanical cyclic stretch in cardiomyocytes increased leptin expression mediated by the induction of AngII, ROS and the ERK pathway to cause cardiomyocyte hypertrophy. Myocardial hypertrophy can be identified by increased transcriptional activity and an enhanced hypertrophic phenotype of cardiomyocytes.
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Research Article|
December 11 2013
Angiotensin II and the ERK pathway mediate the induction of leptin by mechanical cyclic stretch in cultured rat neonatal cardiomyocytes
Chiung-Zuan Chiu;
Chiung-Zuan Chiu
*School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan, Republic of China
†Division of Cardiology, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, Republic of China
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Bao-Wei Wang;
Bao-Wei Wang
*School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan, Republic of China
†Division of Cardiology, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, Republic of China
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Kou-Gi Shyu
†Division of Cardiology, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, Republic of China
‡Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, Republic of China
Correspondence: Professor Kou-Gi Shyu (email m004401@yahoo.com.tw).
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Publisher: Portland Press Ltd
Received:
May 15 2013
Revision Received:
September 03 2013
Accepted:
September 24 2013
Accepted Manuscript online:
September 24 2013
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2014 Biochemical Society
2014
Clin Sci (Lond) (2014) 126 (7): 483–495.
Article history
Received:
May 15 2013
Revision Received:
September 03 2013
Accepted:
September 24 2013
Accepted Manuscript online:
September 24 2013
Citation
Chiung-Zuan Chiu, Bao-Wei Wang, Kou-Gi Shyu; Angiotensin II and the ERK pathway mediate the induction of leptin by mechanical cyclic stretch in cultured rat neonatal cardiomyocytes. Clin Sci (Lond) 1 April 2014; 126 (7): 483–495. doi: https://doi.org/10.1042/CS20130235
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