Simvastatin inhibits angiotensin II-induced cardiac cell hypertrophy: role of Homer 1a.

Abstract

1. The scaffolding protein Homer 1a is constitutively expressed in the myocardium, although its function in cardiomyocytes remains poorly understood. The aim of the present study was to investigate Homer 1a expression in hypertrophic cardiac cells and its role in angiotensin (Ang) II-induced cardiac hypertrophy. 2. After serum starvation for 24 h, cells were treated with 1 micromol/L simvastatin, 100 nmol/L angiotensin (Ang) II or their combination added to Dulbecco's modified Eagle's medium containing 0.5% serum. For combination treatment with AngII plus simvastatin, cells were exposed to simvastatin 12 h before the addition of AngII to the medium and cells were then incubated in the presence of both drugs for a further 24 h. Western blotting was used to determine Homer 1a protein expression. Hypertrophy was evaluated by determining the protein content per cell. 3. Homer 1a protein levels were upregulated following AngII-induced hypertrophy in H9C2 cells and neonatal rat cardiomyocytes, and these increases were augmented by simvastatin pretreatment. Concomitantly, simvastatin pretreatment inhibited extracellular signal-regulated kinase (ERK) 1/2 phosphorylation and AngII-induced hypertrophy. 4. The inhibitory effects of simvastatin against AngII-induced hypertrophy were attenuated by Homer 1a silencing, suggesting that simvastatin suppresses cardiac hypertrophy in a Homer 1a-dependent manner. Furthermore, AngII-induced hypertrophy and ERK1/2 phosphorylation in neonatal rat cardiomyocytes were significantly inhibited following the overexpression of Homer 1a using an adenovirus. 5. These results suggest a possible role for Homer 1a in inhibiting cardiac hypertrophy perhaps in part through inhibition of ERK1/2 activation.

• Authors: Wan-Gang Guo, Fei-Fei Su, Li-Jun Yuan, Guo-Dong Yang, Xiao-Qin Shi, Ruo-Yu Li, Qing Shu, Xiong-Tao Liu, Zi-Fan Lu, Qiang-Sun Zheng
• Journal: Clinical and experimental pharmacology & physiology (Clin Exp Pharmacol Physiol) Vol. 37 Issue 1 Pg. 40-5 (Jan 2010) ISSN: 1440-1681 [Electronic] Australia
• PMID: 19515066 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticholesteremic Agents
• Carrier Proteins
• Homer Scaffolding Proteins
• RNA, Small Interfering
• Angiotensin II
• Simvastatin
• Extracellular Signal-Regulated MAP Kinases

Topics

• Angiotensin II (administration & dosage, antagonists & inhibitors, pharmacology)
• Animals
• Animals, Newborn
• Anticholesteremic Agents (administration & dosage, pharmacology)
• Cardiomegaly (chemically induced, drug therapy, metabolism, physiopathology)
• Carrier Proteins (physiology)
• Cell Line
• Drug Interactions
• Drug Therapy, Combination
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Homer Scaffolding Proteins
• Myocytes, Cardiac (metabolism)
• Phosphorylation (drug effects)
• RNA, Small Interfering (administration & dosage, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Simvastatin (administration & dosage, pharmacology)
• Transfection (methods)
• Up-Regulation