Angiotensin II-mediated oxidative stress and procollagen-1 expression in cardiac fibroblasts: blockade by pravastatin and pioglitazone
Angiotensin II-mediated oxidative stress and procollagen-1 expression in cardiac fibroblasts: blockade by pravastatin and pioglitazone
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DOI：
10.1152/ajpheart.00341.2006
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发表时间：
2006-10-01
影响因子：
4.8
通讯作者：
Mehta, Jawahar L.
中科院分区：
文献类型：
--
作者：
Chen, Jiawei;Mehta, Jawahar L.
血管紧张素II(Ang II)是肾素-血管紧张素系统激活的产物，它促进胶原合成，是心肌梗死后心脏重塑的关键事件。抑制心脏重构现在是多种治疗的目标，包括3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂，通常被称为他汀类药物，以及过氧化物酶体增殖物激活的受体-伽马(PPAR-伽马)配体。我们研究了他汀类药物(普伐他汀)和PPAR-γ配体(吡格列酮)联合应用对血管紧张素转换酶II处理的小鼠心脏成纤维细胞的潜在抗纤维化作用。血管紧张素转换酶II诱导前胶原-1的表达，普伐他汀和吡格列酮以剂量依赖方式抑制其表达。低治疗浓度的普伐他汀(0.1 mU M)或吡格列酮(5 MU M)仅轻微抑制Ang II诱导的NADPH氧化酶表达、超氧阴离子生成和前胶原蛋白1的表达；但联合应用普伐他汀和吡格列酮可显著调节Ang II的上述作用，并阻断Ang II介导的p38MAPK和p44/42MAPK激活。凝胶迁移率改变分析显示Ang II激活了转录因子核因子-kappaB和激活蛋白-1(AP-1)。尽管普伐他汀和吡格列酮单独对核因子-kappaB和AP-1的激活有不同的影响，但它们联合使用对核因子-kappaB和AP-1的激活都有很强的抑制作用。普伐他汀和吡格列酮合用对超氧化物生成和前胶原-1表达的影响与α-生育酚和γ-生育酚相似，表明普伐他汀和吡格列酮在调节Ang II介导的氧化应激、抑制MAPK激活和前胶原-1表达方面存在正向交互作用。
Angiotensin II (ANG II), a product of renin-angiotensin system activation, enhances collagen synthesis, which is a key event in cardiac remodeling after myocardial infarction. Inhibition of cardiac remodeling is now a target of multiple therapies, including 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, commonly known as statins, and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands. We examined the potential antifibrotic effect of the combination of a statin (pravastatin) and a PPAR-gamma ligand (pioglitazone) in ANG II-treated mouse cardiac fibroblasts. ANG II treatment induced procollagen-1 expression, which was inhibited by pravastatin and pioglitazone in a dose-dependent fashion. Pretreatment of fibroblasts with low therapeutic concentrations of either pravastatin (0.1 mu M) or pioglitazone (5 mu M) only slightly decreased ANG II-induced NADPH oxidase expression, superoxide anion production, and procollagen-1 expression; however, the combination of pravastatin and pioglitazone markedly modulated these effects of ANG II. The combination also blocked ANG II-mediated p38 MAPK and p44/42 MAPK activation. Electrophoretic mobility shift assay showed that ANG II activated transcription factors NF-kappa B and activator protein-1 (AP-1). Although pravastatin and pioglitazone alone had a variable effect on NF-kappa B and AP-1 activation, their combination exerted a potent inhibitory effect on the activation of both NF-kappa B and AP-1. The effects of pravastatin and pioglitazone in combination on superoxide generation and procollagen-1 expression mimicked those of alpha-tocopherol and gamma-tocopherol, two potent antioxidants.Thus it appears that there is a positive interaction between pravastatin and pioglitazone in modulating ANG II-mediated oxidative stress, inhibiting MAPK activation, and procollagen-1 expression.