Canadian Centre for Agri-Food Research in Health and Medicine, Winnipeg, Canada.
Eur J Pharmacol. 2011 Oct 1;668(1-2):217-24. doi: 10.1016/j.ejphar.2011.06.042. Epub 2011 Jul 6.
Increased adrenergic drive is a major factor influencing the development of pathological cardiac hypertrophy, a stage which precedes overt heart failure. We examined the effect of resveratrol, a polyphenol (found predominantly in grapes), in preventing norepinephrine induced hypertrophy of adult cardiomyocyte, and the role of nitric oxide (NO) and adenosine monophosphate kinase (AMPK) in the effects of resveratrol. Cardiomyocytes isolated from adult rats were pretreated, or not, with resveratrol and then exposed to norepinephrine for 24h. In other experiments cardiomyocytes were also treated with different pharmacological inhibitors of NO synthase, AMPK and sirtuin for elucidating the signaling pathways underlying the effect of resveratrol. In order to validate the role of these signaling molecules in the in vivo settings, we also examined hearts from resveratrol treated spontaneously hypertensive rats (SHR), a genetic model of essential hypertension. Cardiomyocyte hypertrophy was determined by morphometry and (3)H-phenylalanine incorporation assay. NO levels and AMPK activity were measured using a specific assay kit and western blot analysis respectively. In vitro, resveratrol prevented the norepinephrine-induced increase in cardiomyocytes size and protein synthesis. Pharmacological inhibition of NO-AMPK signaling abolished the anti-hypertrophic action of resveratrol. Consistent with the in vitro findings, the anti-hypertrophic effect of resveratrol in the SHR model was associated with increases in NO and AMPK activity. This study demonstrates that NO-AMPK signaling is linked to the anti-hypertrophic effect of resveratrol in adult cardiomyocytes in vitro, and in the SHR model in vivo.
肾上腺素能驱动增加是影响病理性心肌肥大发展的一个主要因素，而病理性心肌肥大是心力衰竭之前的一个阶段。我们研究了白藜芦醇（一种主要存在于葡萄中的多酚）在预防去甲肾上腺素诱导的成年心肌细胞肥大中的作用，以及一氧化氮（NO）和单磷酸腺苷激酶（AMPK）在白藜芦醇作用中的作用。从成年大鼠分离的心肌细胞用或不用白藜芦醇预处理，然后用去甲肾上腺素孵育 24 小时。在其他实验中，还使用不同的 NO 合酶、AMPK 和沉默调节蛋白抑制剂处理心肌细胞，以阐明白藜芦醇作用的信号通路。为了验证这些信号分子在体内环境中的作用，我们还检查了白藜芦醇处理的自发性高血压大鼠（SHR）的心脏，SHR 是一种原发性高血压的遗传模型。通过形态计量学和（3）H-苯丙氨酸掺入测定来确定心肌细胞肥大。使用特定的测定试剂盒和 Western blot 分析分别测量 NO 水平和 AMPK 活性。在体外，白藜芦醇可预防去甲肾上腺素诱导的心肌细胞大小和蛋白质合成增加。NO-AMPK 信号通路的药理学抑制消除了白藜芦醇的抗肥大作用。与体外研究结果一致，白藜芦醇在 SHR 模型中的抗肥大作用与 NO 和 AMPK 活性的增加有关。这项研究表明，NO-AMPK 信号通路与白藜芦醇在体外成年心肌细胞和体内 SHR 模型中的抗肥大作用有关。
