Attenuation of cardiac dysfunction by a PPAR-α agonist is associated with down-regulation of redox-regulated transcription factors
Attenuation of cardiac dysfunction by a PPAR-α agonist is associated with down-regulation of redox-regulated transcription factors
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DOI：
10.1016/j.yjmcc.2006.05.013
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发表时间：
2006-08-01
影响因子：
5
通讯作者：
Yokota, Mitsuhiro
中科院分区：
文献类型：
--
作者：
Ichihara, Sahoko;Obata, Koji;Yokota, Mitsuhiro
过氧化物酶体增殖激活受体-a （PPAR-et）是脂质和葡萄糖代谢的关键调节因子，并与炎症有关。我们研究了ppar - α激活剂非诺贝特对达尔盐敏感（DS）大鼠左室（LV）肥厚和心力衰竭发展的影响，以及氧化还原调节转录因子的作用。从7周龄开始，给DS大鼠喂食高盐饮食，并给予非诺贝特（30或50 mg/kg /天）或载药。非诺贝特抑制代偿性高血压性左室肥厚的发展，减轻左室舒张异常和收缩功能障碍，提高DS大鼠生存率。它还可以防止高盐饮食诱导的还原谷胱甘肽与氧化谷胱甘肽的比例下降，抑制氧化还原调节转录因子NF-kappa B、AP-1、Egr-1、SP1和Ets-1在左心室DNA结合活性的上调。这些转录因子靶基因的表达，包括粘附分子（VCAM-1、ICAM-1）、细胞因子（MCP-1）、生长因子（tgf - β、PDGF-B）和骨桥蛋白，也在高盐饮食中以对非诺贝特治疗敏感的方式增加。此外，非诺贝特还能抑制巨噬细胞和T淋巴细胞向左心室的浸润以及血浆c反应蛋白浓度的升高。ppar - α激活剂非诺贝特因此减轻了心力衰竭的进展，提高了该大鼠模型的存活率。这些作用与左心室炎症反应的抑制和氧化还原调节的转录因子的激活有关。(c) 2006爱思唯尔公司版权所有。
Peroxisome prolifierator-activated receptor-a (PPAR-et) is a key regulator of lipid and glucose metabolism and is implicated in inflammation. We investigated the effects of the PPAR-alpha activator fenofibrate on, as well as the role of redox-regulated transcription factors, in the development of left ventricular (LV) hypertrophy and heart failure in Dahl salt-sensitive (DS) rats. DS rats were fed a high-salt diet and treated with either fenofibrate (30 or 50 mg/kg per day) or vehicle from 7 weeks of age. Fenofibrate inhibited the development of compensated hypertensive LV hypertrophy, attenuated the LV relaxation abnormality and systolic dysfunction, and improved the survival rate in DS rats. It also prevented a decrease in the ratio of reduced to oxidized glutathione and inhibited up-regulation of the DNA binding activities of the redox-regulated transcription factors NF-kappa B, AP-1, Egr-1, SP1, and Ets-1 induced in the left ventricle by the high-salt diet. Expression of target genes for these transcription factors, including those for adhesion molecules (VCAM-1, ICAM-1), cytokines (MCP-1), growth factors (TGF-beta, PDGF-B), and osteopontin, was also increased by the high-salt diet in a manner sensitive to treatment with fenofibrate. Furthermore, the infiltration of macrophages and T lymphocytes into the left ventricle and the increase in the plasma concentration of C-reactive protein were inhibited by fenofibrate. The PPAR-alpha activator fenofibrate thus attenuated the progression of heart failure and improved the survival rate in this rat model. These effects were associated with inhibition of the inflammatory response and of activation of redox-regulated transcription factors in the left ventricle. (c) 2006 Elsevier Inc. All rights reserved.