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Use of atorvastatin to inhibit hypoxia‐induced myocardin expression
Author(s) -
Chiu ChiungZuan,
Wang BaoWei,
Shyu KouGi
Publication year - 2012
Publication title -
european journal of clinical investigation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.164
H-Index - 107
eISSN - 1365-2362
pISSN - 0014-2972
DOI - 10.1111/j.1365-2362.2011.02628.x
Subject(s) - myocardin , serum response factor , mapk/erk pathway , atorvastatin , microbiology and biotechnology , hypoxia (environmental) , chemistry , transcription factor , signal transduction , biology , pharmacology , biochemistry , oxygen , gene , organic chemistry
Eur J Clin Invest 2012; 42 (5): 564–571 Abstract Background Hypoxia induces the formation of reactive oxygen species (ROS), myocardin expression and cardiomyocyte hypertrophy. The 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors (statins) have been demonstrated to have both antioxidant and antihypertrophic effects. We evaluated the pathways of atorvastatin in repressing ROS and myocardin after hypoxia to prevent cardiomyocyte hypertrophy. Materials and methods Cultured rat neonatal cardiomyocytes were subjected to hypoxia, and the expression of myocardin and ROS were evaluated. Different signal transduction inhibitors, atorvastatin and N‐acetylcysteine (NAC) were used to identify the pathways that inhibited myocardin expression and ROS. Electrophoretic motility shift assay (EMSA) and luciferase assay were used to identify the binding of myocardin/serum response factor (SRF) and transcription to cardiomyocytes. Cardiomyocyte hypertrophy was assessed by 3 H‐proline incorporation assay. Results Myocardin expression after hypoxia was inhibited by atorvastatin, RhoA/Rho kinase inhibitor (Y27632), extracellular signal‐regulated kinase (ERK) small interfering RNA (siRNA)/ERK pathway inhibitor (PD98059), myocardin siRNA and NAC. Bindings of myocardin/SRF, transcription of myocardin/SRF to cardiomyocytes, presence of myocardin in the nuclei of cardiomyocytes and protein synthesis after hypoxia were identified by EMSA, luciferase assay, confocal microscopy and 3 H‐proline assay and were suppressed by atorvastatin, Y27632, PD98059 and NAC. Conclusions Hypoxia in neonatal cardiomyocytes increases myocardin expression and ROS to cause cardiomyocyte hypertrophy, which can be prevented by atorvastatin by suppressing ROS and myocardin expression.