Dong Ming, Ding Wenwen, Liao Yansong, Liu Ye, Yan Dewen, Zhang Yi, Wang Rongming, Zheng Na, Liu Shuaiye, Liu Jie
Medical College, Shenzhen University, Shenzhen 518000, Guangdong, China.
Department of Pathophysiology, Southern Medical University, Guangzhou 510515, China.
Eur J Pharmacol. 2015 Jan 5;746:186-97. doi: 10.1016/j.ejphar.2014.11.012. Epub 2014 Nov 20.
Recent evidence suggests that polydatin (PD), a resveratrol glucoside, may have beneficial actions on the cardiac hypertrophy. Therefore, the current study focused on the underlying mechanism of the PD anti-hypertrophic effect in cultured cardiomyocytes and in progression from cardiac hypertrophy to heart failure in vivo. Experiments were performed on cultured neonatal rat, ventricular myocytes as well as adult mice subjected to transverse aortic constriction (TAC). Treatment of cardiomyocytes with phenylephrine for three days produced a marked hypertrophic effect as evidenced by significantly increased cell surface area and atrial natriuretic peptide (ANP) protein expression. These effects were attenuated by PD in a concentration-dependent manner with a complete inhibition of hypertrophy at the concentration of 50 µM. Phenylephrine increased ROCK activity, as well as intracellular reactive oxygen species production and lipid peroxidation. The oxidizing agent DTDP similarly increased Rho kinase (ROCK) activity and induced hypertrophic remodeling. PD treatment inhibited phenylephrine-induced oxidative stress and consequently suppressed ROCK activation in cardiomyocytes. Hypertrophic remodeling and heart failure were demonstrated in mice subjected to 13 weeks of TAC. Upregulation of ROCK signaling pathway was also evident in TAC mice. PD treatment significantly attenuated the increased ROCK activity, associated with a markedly reduced hypertrophic response and improved cardiac function. Our results demonstrated a robust anti-hypertrophic remodeling effect of polydatin, which is mediated by inhibition of reactive oxygen species dependent ROCK activation.
最近的证据表明，白藜芦醇苷（PD）可能对心肌肥大具有有益作用。因此，本研究聚焦于PD在培养的心肌细胞中抗肥大作用的潜在机制，以及在体内从心肌肥大发展至心力衰竭过程中的作用机制。实验在培养的新生大鼠心室肌细胞以及接受主动脉缩窄（TAC）的成年小鼠上进行。用去甲肾上腺素处理心肌细胞三天产生了明显的肥大效应，表现为细胞表面积和心房利钠肽（ANP）蛋白表达显著增加。这些效应被PD以浓度依赖的方式减弱，在50μM浓度时完全抑制肥大。去甲肾上腺素增加了ROCK活性，以及细胞内活性氧的产生和脂质过氧化。氧化剂DTDP同样增加了Rho激酶（ROCK）活性并诱导了肥大重塑。PD处理抑制了去甲肾上腺素诱导的氧化应激，从而抑制了心肌细胞中的ROCK激活。在接受13周TAC的小鼠中出现了肥大重塑和心力衰竭。ROCK信号通路的上调在TAC小鼠中也很明显。PD处理显著减弱了增加的ROCK活性，同时肥大反应明显降低，心脏功能得到改善。我们的结果证明了白藜芦醇苷具有强大的抗肥大重塑作用，这是通过抑制活性氧依赖性ROCK激活介导的。
