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Published on: June 3, 2018
Metformin suppresses phenylephrine-induced hypertrophic responses by inhibiting p300-HAT activity in cardiomyocytes
Yoichi Sunagawa1, Kiyotaka Shimizu2, Ayumi Katayama2
1Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, 422-8526, Japan; Division of Translational Research, Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, Kyoto, 612-8555, Japan; Shizuoka General Hospital, Shizuoka, 420-8527, Japan.
Insights
Metformin suppresses cardiac hypertrophy by inhibiting p300-histone acetyltransferase (HAT) activity. This finding suggests metformin may benefit patients with heart failure and diabetes.
Area of Science:
- Cardiology
- Molecular Biology
- Pharmacology
Background:
- Heart failure results from various myocardial stressors like hypertension and infarction.
- The impact of metformin on cardiac hypertrophy remains largely unknown.
Purpose of the Study:
- To determine if metformin inhibits hypertrophic responses in cardiomyocytes.
- To investigate metformin's effect on p300-histone acetyltransferase (HAT) activity.
Main Methods:
- In vitro HAT assay to assess p300 inhibition by metformin.
- Cardiomyocyte treatment with metformin and phenylephrine (PE) to evaluate hypertrophic markers.
- Analysis of gene expression, cell size, and histone acetylation.
Main Results:
- Metformin directly inhibited p300-mediated histone-H3K9 acetylation.
- Phenylephrine-induced cardiac hypertrophy, including increased cell size and specific gene expression, was suppressed by metformin.
- Metformin also inhibited p300-induced hypertrophic responses and histone acetylation.
Conclusions:
- Metformin effectively suppresses phenylephrine-induced and p300-mediated cardiac hypertrophy.
- Metformin demonstrates potential therapeutic value for patients with diabetes and heart failure.
Introduction:
Heart failure is the final pathway for a wide spectrum of myocardial stress, including hypertension and myocardial infarction. However, the potential effects of metformin on cardiac hypertrophy are still unclear.
Purpose:
The purpose of this study was to investigate whether metformin leads to suppression of hypertrophic responses in cardiomyocytes.
Methods And Results:
To investigate whether metformin inhibited p300-histone acetyltransferase (HAT), we performed an in vitro HAT assay. Metformin directly inhibited p300-mediated acetylation of histone-H3K9. To examine the effects of metformin on hypertrophic responses, cardiomyocytes prepared from neonatal rats were treated with metformin and stimulated with saline or phenylephrine (PE), a α1-adrenergic agonist for 48 h. PE stimulus showed an increase in cell size, myofibrillar organization, expression of the endogenous atrial natriuretic factor and brain natriuretic peptide genes, and acetylation of histone-H3K9 compared with saline-treated cells. These PE-induced changes were inhibited by metformin. Next, to examine the effect of metformin on p300-mediated hypertrophy, cardiomyocytes were transfected with expression vector of p300. Metformin significantly suppressed p300-induced hypertrophic responses and acetylation of histone-H3K9.
Conclusions:
The study demonstrates that metformin can suppress PE-induced and p300-mediated hypertrophic responses. Metformin may be useful for the treatment of patients with diabetes and heart failure.
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