OBJECTIVE: The purpose of this study was to investigate whether metformin leads to suppression of hypertrophic responses in cardiomyocytes.
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.
目的:本研究的目的是研究二甲双胍是否能抑制心肌细胞的肥大反应。
结果:为了研究二甲双胍是否抑制p300-组蛋白乙酰转移酶(HAT),我们进行了体外HAT测定。二甲双胍直接抑制p300介导的组蛋白-H3K9的乙酰化。为了检查二甲双胍对肥大反应的影响,用二甲双胍治疗新生大鼠心肌细胞并用生理盐水或去氧肾上腺素(PE)刺激,α1-肾上腺素能激动剂48小时。PE刺激显示细胞大小增加,肌原纤维组织,内源性心钠素和脑钠肽基因的表达,与盐水处理的细胞相比,组蛋白-H3K9的乙酰化。这些PE诱导的变化被二甲双胍抑制。接下来,为了检查二甲双胍对p300介导的肥大的影响,用p300表达载体转染心肌细胞。二甲双胍显着抑制p300诱导的肥大反应和组蛋白H3K9的乙酰化。
结论:研究表明二甲双胍可以抑制PE诱导的和p300介导的肥大反应。二甲双胍可用于糖尿病和心力衰竭患者的治疗。