Angiotensin II increases periostin expression via Ras/p38 MAPK/CREB and ERK1/2/TGF-β1 pathways in cardiac fibroblasts
Angiotensin II increases periostin expression via Ras/p38 MAPK/CREB and ERK1/2/TGF-β1 pathways in cardiac fibroblasts
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DOI：
10.1093/cvr/cvr067
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发表时间：
2011-07-01
影响因子：
10.8
通讯作者：
Wu, Li-Ling
中科院分区：
文献类型：
--
作者：
Li, Li;Fan, Dong;Wu, Li-Ling
目的血管紧张素II（AngII）参与细胞外基质（ECM）的积聚，导致心力衰竭.骨膜蛋白是一种90 kDa ECM蛋白，是心脏纤维化的关键调节因子，其表达在衰竭心脏中显著更高。我们确定了AngII对periostin水平的调节作用，并探讨了可能的信号转导mechanism.Methods和结果AngII（400 ng/kg/min）或生理盐水皮下注射28天到大鼠; AngII拮抗与氯沙坦（10 mg/kg/天口服）。血管紧张素II输注诱导心脏纤维化和增加periostin的表达，这是由氯沙坦减弱。在培养的成年大鼠心脏成纤维细胞中，AngII促进periostin的mRNA和蛋白表达。AngII引起cAMP反应元件结合蛋白（CREB）的激活，CREB小干扰RNA（siRNA）抑制AngII诱导的骨膜蛋白表达。用SB 202190抑制p38丝裂原活化蛋白激酶（p38 MAPK）减弱AngII诱导的CREB活化和骨膜蛋白表达。转染Ras鸟苷酸释放蛋白1 siRNA或RasN 17显性阴性质粒可抑制AngII诱导的p38 MAPK磷酸化和骨膜蛋白表达。转化生长因子（TGF）-β 1抗体降低AngII对骨膜蛋白表达的刺激作用。细胞外信号调节激酶1/2（ERK 1/2）抑制剂PD 98059可抑制AngII诱导的TGF-β 1表达、Smad 2/3核积聚和periostin表达。结论Ras/p38 MAPK/CREB通路的激活是AngII诱导periostin表达的必要条件。ERK 1/2还通过调节TGF-β 1/Smad信号通路参与AngII诱导的骨膜蛋白表达。
Aims Angiotensin II (AngII) is involved in extracellular matrix (ECM) accumulation contributing to heart failure. Periostin, a 90 kDa ECM protein, is a key regulator of cardiac fibrosis, and its expression is significantly higher in failing hearts. We determined the modulatory effect of AngII on periostin level and explored the possible signal transduction mechanism.Methods and results AngII (400 ng/kg/min) or normal saline was infused subcutaneously for 28 days into rats; AngII antagonism was with losartan (10 mg/kg/day orally). AngII infusion induced cardiac fibrosis and increased periostin expression, which was attenuated by losartan. In cultured adult rat cardiac fibroblasts, AngII promoted the mRNA and protein expression of periostin. AngII provoked activation of cAMP response element-binding protein (CREB), and CREB small interfering RNA (siRNA) suppressed AngII-induced periostin expression. Inhibition of p38 mitogen-activated protein kinase (p38 MAPK) with SB202190 attenuated AngII-induced CREB activation and periostin expression. Transfection with Ras guanyl-releasing protein 1 siRNA or RasN17 dominant-negative plasmid prevented AngII-induced p38 MAPK phosphorylation and periostin expression. Transforming growth factor (TGF)-beta 1 antibody decreased the stimulatory effect of AngII on periostin expression. The extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor PD98059 attenuated AngII-induced TGF-beta 1 expression, Smad2/3 nuclear accumulation, and periostin expression.Conclusion The activation of the Ras/p38 MAPK/CREB pathway is required for AngII-induced periostin expression. ERK1/2 also participates in AngII-induced periostin expression by regulating TGF-beta 1/Smad signalling.