葛根素通过氧化还原敏感的ERK1/2、p38和NF-κB信号通路抑制血管紧张素II诱导的心肌肥大。
Puerarin inhibits angiotensin II-induced cardiac hypertrophy via the redox-sensitive ERK1/2, p38 and NF-κB pathways.
作者信息
Chen Gang, Pan Shi-qi, Shen Cong, Pan Shi-fen, Zhang Xiu-min, He Qi-yang
机构信息
Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China.
The 4th Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
出版信息
Acta Pharmacol Sin. 2014 Apr;35(4):463-75. doi: 10.1038/aps.2013.185. Epub 2014 Mar 10.
AIM
To investigate the effects of puerarin (Pue), an isoflavone derived from Kudzu roots, on angiotensin II (Ang II)-induced hypertrophy of cardiomyocytes in vivo and in vitro.
METHODS
C57BL/6J mice were infused with Ang II and treated with Pue (100 mg·kg(-1)·d(-1), po) for 15 d. After the treatment, systolic blood pressure (SBP) and left ventricular wall thickness were assessed. The ratios of heart weight to body weight (HW/BW) and left ventricular weight to body weight (LVW/BW) were determined, and heart morphometry was assessed. Expression of fetal-type genes (ANP, BNP and β-MHC) in left ventricles was measured using semi-quantitative RT-PCR. Mouse primary cardiomyocytes were treated with Pue (50, 100, 200 μmol/L), then exposed to Ang II (1 μmol/L). ROS level was examined with flow cytometry, the binding activity of NF-κB was determined using EMSA. Western blot was used to measure the levels of ERK1/2, p38 and NF-κB pathway proteins. [(3)H]leucine incorporation was used to measure the rate of protein synthesis.
RESULTS
Oral administration of Pue significantly suppressed Ang II-induced increases in the myocyte surface area, HW/BW, LVW/BW, SBP and left ventricular wall thickness. Furthermore, Pue significantly suppressed Ang II-induced increases in ANP, BNP and β-MHC expression in the left ventricles in vivo. Treatment of cardiomyocytes with Pue (50-500 μmol/L) did not affect the viability of cardiomyocytes in vitro. Pretreatment of cardiomyocytes with Pue dose-dependently inhibited Ang II-induced increases in ROS production, NF-κB binding activity, protein synthesis and cell breadth. Furthermore, pretreatment with Pue significantly suppressed Ang II-induced activation of ERK1/2, p38 and the NF-κB pathway proteins and the expression of ANP and β-MHC in cardiomyocytes. The positive drug valsartan exerted similar effects on Ang II-induced cardiac hypertrophy in vivo and in vitro.
CONCLUSION
Pue attenuates Ang II-induced cardiac hypertrophy by inhibiting activation of the redox-sensitive ERK1/2, p38 and the NF-κB pathways.
目的
研究葛根中提取的异黄酮葛根素（Pue）对体内外血管紧张素II（Ang II）诱导的心肌细胞肥大的影响。
方法
给C57BL/6J小鼠输注Ang II，并给予Pue（100 mg·kg⁻¹·d⁻¹，口服）治疗15天。治疗后，评估收缩压（SBP）和左心室壁厚度。测定心脏重量与体重之比（HW/BW）和左心室重量与体重之比（LVW/BW），并评估心脏形态学。使用半定量RT-PCR检测左心室中胎儿型基因（ANP、BNP和β-MHC）的表达。用Pue（50、100、200 μmol/L）处理小鼠原代心肌细胞，然后暴露于Ang II（1 μmol/L）。用流式细胞术检测ROS水平，用EMSA测定NF-κB的结合活性。用蛋白质印迹法检测ERK1/2、p38和NF-κB信号通路蛋白的水平。用[³H]亮氨酸掺入法测定蛋白质合成速率。
结果
口服Pue可显著抑制Ang II诱导的心肌细胞表面积、HW/BW、LVW/BW、SBP和左心室壁厚度增加。此外，Pue可显著抑制Ang II诱导的体内左心室中ANP、BNP和β-MHC表达增加。用Pue（50 - 500 μmol/L）处理心肌细胞对体外心肌细胞活力无影响。用Pue预处理心肌细胞可剂量依赖性地抑制Ang II诱导的ROS产生增加、NF-κB结合活性、蛋白质合成和细胞宽度增加。此外，用Pue预处理可显著抑制Ang II诱导的心肌细胞中ERK1/2、p38和NF-κB信号通路蛋白的激活以及ANP和β-MHC的表达。阳性药物缬沙坦对体内外Ang II诱导的心脏肥大具有相似的作用。
结论
Pue通过抑制氧化还原敏感的ERK1/2、p38和NF-κB信号通路激活来减轻Ang II诱导的心脏肥大。
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