Angiotensin II regulation of collagen type I expression in cardiac fibroblasts -: Modulation by PPAR-γ ligand pioglitazone
Angiotensin II regulation of collagen type I expression in cardiac fibroblasts -: Modulation by PPAR-γ ligand pioglitazone
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DOI：
10.1161/01.hyp.0000144400.49062.6b
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发表时间：
2004-11-01
期刊：
影响因子：
8.3
通讯作者：
Mehta, JL
中科院分区：
文献类型：
--
作者：
Chen, K;Chen, JW;Mehta, JL
血管紧张素II(Ang II)介导的对成纤维细胞生长和I型胶原合成的刺激被认为是高血压和慢性缺血心脏重构过程中的重要组成部分。Ang II介导的氧化应激可能在促进成纤维细胞生长和胶原形成中起重要作用。因此，我们推测PPAR-γ配体吡格列酮可以改变Ang II诱导的心脏成纤维细胞中I型胶原的形成。用不同浓度(10(-8)~10(-6)M)的Ang II处理心脏成纤维细胞不同时间(6小时、12小时和24小时)。Ang II以浓度和时间依赖的方式增加I型胶原的表达(P<；0.01与对照组相比)。血管紧张素转换酶II还可降低基质金属蛋白酶-1的表达和活性(与对照组比较，P<0.05)。血管紧张素Ⅱ的上述作用可被吡格列酮(10mumol/L)预处理细胞所减弱。血管紧张素转换酶II刺激细胞内产生活性氧(ROS)，这种作用可被吡格列酮减弱。Ang II可激活氧化还原敏感的转录因子NF-kappaB，而吡格列酮可阻断Ang II的这一作用。Ang II还可激活另一转录因子AP-1，但Ang II的这一作用不受吡格列酮的调节。在其他实验中，我们观察到维生素E的水溶性类似物曲洛克斯以类似于吡格列酮的方式减弱了Ang II对I型胶原和基质金属蛋白酶-1表达的影响。因此，吡格列酮抑制血管紧张素Ⅱ介导的心脏成纤维细胞I型胶原的合成。吡格列酮的作用是通过调节ROS释放和氧化还原敏感的转录因子NF-kappaB来实现的。
Angiotensin II (Ang II)-mediated stimulation of fibroblast growth and collagen type I synthesis is believed to be an important component of the cardiac remodeling process in hypertension and chronic ischemia. Ang II-mediated oxidative stress could be important in enhanced fibroblast growth and collagen formation. Accordingly, we postulated that the PPAR-gamma ligand, pioglitazone, which is known to modulate oxidative stress, would alter Ang II-induced formation of collagen type I in cardiac fibroblasts. Cardiac fibroblasts were treated with different concentrations (10(-8) to 10(-6) M) of Ang II for different times (6 hours, 12 hours, and 24 hours). Ang II increased the expression of collagen type I in a concentration- and time-dependent fashion (P < 0.01 versus control). Ang II also decreased the expression and activity of matrix metalloproteinase (MMP)-1 (MMP-1, P < 0.05 versus control). These effects of Ang II were attenuated by pretreatment of cells with pioglitazone (10 mumol/L). Ang II stimulated the intracellular generation of reactive oxygen species (ROS), and this effect was also attenuated by pioglitazone. Ang II treatment activated the redox-sensitive transcription factor NF-kappaB, and pioglitazone pretreatment blocked this effect of Ang II. Ang II also activated another transcription factor, AP-1, but this effect of Ang II was not modulated by pioglitazone. In other experiments, we observed that trolox, the water soluble analog of vitamin E, attenuated the effects of Ang II on the expression of collagen type I and MMP-1, in a manner similar to pioglitazone. Thus, pioglitazone attenuates Ang II-mediated collagen type I synthesis in cardiac fibroblasts. The effects of pioglitazone are mediated by the modulation of ROS release and redox-sensitive transcription factor NF-kappaB.