Angiotensin II and the ERK pathway mediate the induction of leptin by mechanical cyclic stretch in cultured rat neonatal cardiomyocytes

作者：Chiu Chiung Zuan; Wang Bao Wei; Shyu Kou Gi^*

来源：Clinical Science, 2014, 126(7-8): 483-495.

DOI：10.1042/CS20130235

• angiotensin II
• cardiomyocyte hypertrophy
• extracellular signal-regulated kinase (ERK)
• leptin
• reactive oxygen species (ROS)
• transcriptional activity

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 Angll (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 Angll expression. Leptin and leptin receptor levels increased after cyclic stretch with the earlier expression of Angll and ROS. Leptin expression was suppressed by Angll 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 [H-3]-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 Angll expression after cyclic stretch. Mechanical cyclic stretch in cardiomyocytes increased leptin expression mediated by the induction of Angll, 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.

• 出版日期2014-4