Retinoic acid receptor-mediated signaling protects cardiomyocytes from hyperglycemia induced apoptosis: role of the renin-angiotensin system.
Retinoic acid receptor-mediated signaling protects cardiomyocytes from hyperglycemia induced apoptosis: role of the renin-angiotensin system.
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DOI：
10.1002/jcp.22457
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发表时间：
2011-05
影响因子：
5.6
通讯作者：
Pan, Jing
中科院分区：
文献类型：
--
作者：
Guleria, Rakeshwar S.;Choudhary, Rashmi;Tanaka, Takemi;Baker, Kenneth M.;Pan, Jing
糖尿病是心血管疾病和心力衰竭的主要危险因素。激活维甲酸受体（RAR）和类维甲酸X受体（RXR）具有抗糖尿病作用；但是，它在糖尿病性心肌病中的作用尚不清楚。利用新生儿和成人心肌细胞，我们确定了RAR和RXR在高血糖诱导的细胞凋亡和肾素-血管紧张素系统（RAS）成分表达中的作用。HG处理的ZDF大鼠新生儿、成人心肌细胞和糖尿病心脏中RARα和RXRα的核表达降低，凋亡信号激活和细胞凋亡。RAR和RXR激动剂均可阻止hg诱导的细胞凋亡和活性氧（ROS）的产生。通过小干扰RNA沉默RARα和RXRα的表达，在正常情况下促进细胞凋亡，并显著增强hg诱导的细胞凋亡，表明RARα和RXRα在细胞凋亡信号的调控中是必需的。阻断血管紧张素1型受体（AT1R）；但AT2R不能减弱hg诱导的细胞凋亡和ROS的产生。此外，HG诱导的血管紧张素原、肾素、AT1R和血管紧张素II （Ang II）合成的基因表达被RARα激动剂抑制，而通过沉默RARα促进。激活RXRα，下调AT1R的表达；RXRα沉默可加速HG诱导的血管紧张素原和Ang II的表达，而对肾素基因的表达无显著影响。这些结果表明，RARα和RXRα表达的降低在高血糖介导的细胞凋亡和RAS成分的表达中起重要作用。激活RAR/RXR信号通过减少氧化应激和抑制RAS来保护心肌细胞免受高血糖。
Diabetes mellitus is a primary risk factor for cardiovascular diseases and heart failure. Activation of the retinoic acid receptor (RAR) and retinoid X receptor (RXR) has an anti-diabetic effect; but, a role in diabetic cardiomyopathy remains unclear. Using neonatal and adult cardiomyocytes, we determined the role of RAR and RXR in hyperglycemia-induced apoptosis and expression of renin-angiotensin system (RAS) components. Decreased nuclear expression of RARα and RXRα, activation of apoptotic signaling and cell apoptosis was observed in HG treated neonatal and adult cardiomyocytes and diabetic hearts in ZDF rats. HG-induced apoptosis and reactive oxygen species (ROS) generation was prevented by both RAR and RXR agonists. Silencing expression of RARα and RXRα, by small interference RNA, promoted apoptosis under normal conditions and significantly enhanced HG-induced apoptosis, indicating that RARα and RXRα are required in regulating cell apoptotic signaling. Blocking angiotensin type 1 receptor (AT1R); but, not AT2R, attenuated HG-induced apoptosis and ROS generation. Moreover, HG induced gene expression of angiotensinogen, renin, AT1R and angiotensin II (Ang II) synthesis were inhibited by RARα agonists and promoted by silencing RARα. Activation of RXRα, downregulated the expression of AT1R; and RXRα silencing accelerated HG induced expression of angiotensinogen and Ang II synthesis, whereas there was no significant effect on renin gene expression. These results indicate that reduction in the expression of RARα and RXRα has an important role in hyperglycemia mediated apoptosis and expression of RAS components. Activation of RAR/RXR signaling protects cardiomyocytes from hyperglycemia, by reducing oxidative stress and inhibition of the RAS.
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DOI：
10.1152/ajpheart.01301.2007
发表时间：
2008-02-01
影响因子：
4.8
作者：
Choudhary, Rashmi;Palm-Leis, Ants;Pan, Jing
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DOI：
10.1080/07315724.1997.10718647
发表时间：
1997-02-01
影响因子：
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DOI：
10.1016/0735-1097(93)90455-a
发表时间：
1993-10-01
影响因子：
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HO, KKL;PINSKY, JL;LEVY, D
通讯作者：
LEVY, D
影响因子：
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作者：
Choudhary, Rashmi;Baker, Kenneth M.;Pan, Jing
通讯作者：
Pan, Jing
影响因子：
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作者：
Baker, KM;Chernin, MI;Kumar, R
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Kumar, R