Use of atorvastatin to inhibit hypoxia-induced myocardin expression.

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.

• Authors: Chiung-Zuan Chiu, Bao-Wei Wang, Kou-Gi Shyu
• Journal: European journal of clinical investigation (Eur J Clin Invest) Vol. 42 Issue 5 Pg. 564-71 (May 2012) ISSN: 1365-2362 [Electronic] England
• PMID: 22129233 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 The Authors. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation.

Chemical References

• Heptanoic Acids
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Nuclear Proteins
• Pyrroles
• Reactive Oxygen Species
• Trans-Activators
• myocardin
• Atorvastatin
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Animals, Newborn
• Atorvastatin
• Blotting, Western
• Cells, Cultured
• Electrophoretic Mobility Shift Assay
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Heptanoic Acids (pharmacology)
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Hypertrophy (metabolism)
• Hypoxia (metabolism, prevention & control)
• Myocytes, Cardiac (drug effects, metabolism)
• Nuclear Proteins (metabolism)
• Pyrroles (pharmacology)
• Rats
• Rats, Wistar
• Reactive Oxygen Species (metabolism)
• Real-Time Polymerase Chain Reaction
• Trans-Activators (metabolism)