Resveratrol induces mitochondrial biogenesis and ameliorates Ang II-induced cardiac remodeling in transgenic rats harboring human renin and angiotensinogen genes
Resveratrol induces mitochondrial biogenesis and ameliorates Ang II-induced cardiac remodeling in transgenic rats harboring human renin and angiotensinogen genes
复制标题
DOI：
10.3109/08037051.2010.481808
复制
发表时间：
2010-06-01
期刊：
影响因子：
1.8
通讯作者：
Mervaala, Eero
中科院分区：
文献类型：
--
作者：
Biala, Agnieszka;Tauriainen, Eveliina;Mervaala, Eero
有令人信服的证据表明，增加的局部肾素-血管紧张素系统的活性在心肌肥厚和心力衰竭的发病机制中的重要作用。白藜芦醇是一种天然多酚，可激活SIRT 1，SIRT 1是一种具有NAD（+）依赖性组蛋白脱乙酰酶活性的新型心脏保护和长寿因子。本研究旨在验证白藜芦醇是否能预防血管紧张素II（Ang II）诱导的心血管损伤。用SIRT 1激活剂白藜芦醇或SIRT 1抑制剂烟酰胺对携带人肾素和人血管紧张素原基因（dTGR）的4周龄双转基因大鼠进行4周治疗。未处理的dTGR及其血压正常的Sprague-Dawley对照大鼠（SD）接受溶媒。未经治疗的dTGR发展严重的高血压以及心脏肥大，并显示出显着的心血管死亡率与血压正常的SD大鼠相比。白藜芦醇轻微但显着降低血压，改善心脏肥大，并完全防止血管紧张素II诱导的死亡率，而烟酰胺增加血压没有显着影响心脏肥大或生存。白藜芦醇降低心肌ANP mRNA表达，并诱导心肌线粒体生物发生标志物过氧化物酶体增殖物激活受体-γ共激活因子（PGC-1 α）、线粒体转录因子（Tfam）、核呼吸因子1（NRF-1）和细胞色素c氧化酶亚基4（cox 4）的mRNA表达。白藜芦醇在体外剂量依赖性地增加SIRT 1活性。我们的研究结果表明，SIRT 1激活剂白藜芦醇对血管紧张素II诱导的心脏重塑的有益作用是由血压依赖性途径介导的，并与线粒体生物合成增加有关。
There is compelling evidence to indicate an important role for increased local renin-angiotensin system activity in the pathogenesis of cardiac hypertrophy and heart failure. Resveratrol is a natural polyphenol that activates SIRT1, a novel cardioprotective and longevity factor having NAD(+)-dependent histone deacetylase activity. We tested the hypothesis whether resveratrol could prevent from angiotensin II (Ang II)-induced cardiovascular damage. Four-week-old double transgenic rats harboring human renin and human angiotensinogen genes (dTGR) were treated for 4 weeks either with SIRT1 activator resveratrol or SIRT1 inhibitor nicotinamide. Untreated dTGR and their normotensive Sprague-Dawley control rats (SD) received vehicle. Untreated dTGR developed severe hypertension as well as cardiac hypertrophy, and showed pronounced cardiovascular mortality compared with normotensive SD rats. Resveratrol slightly but significantly decreased blood pressure, ameliorated cardiac hypertrophy and prevented completely Ang II-induced mortality, whereas nicotinamide increased blood pressure without significantly influencing cardiac hypertrophy or survival. Resveratrol decreased cardiac ANP mRNA expression and induced cardiac mRNA expressions of mitochondrial biogenesis markers peroxisome proliferator-activated receptor-gamma coactivator (PGC-1 alpha), mitochondrial transcription factor (Tfam), nuclear respiratory factor 1 (NRF-1) and cytochrome c oxidase subunit 4 (cox4). Resveratrol dose-dependently increased SIRT1 activity in vitro. Our findings suggest that the beneficial effects of SIRT1 activator resveratrol on Ang II-induced cardiac remodeling are mediated by blood pressure-dependent pathways and are linked to increased mitochondrial biogenesis.