P38 MAP kinase mediates inflammatory cytokine induction in cardiomyocytes and extracellular matrix remodeling in heart
P38 MAP kinase mediates inflammatory cytokine induction in cardiomyocytes and extracellular matrix remodeling in heart
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DOI：
10.1161/01.cir.0000165117.71483.0c
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发表时间：
2005-05-17
期刊：
影响因子：
37.8
通讯作者：
Wang, YB
中科院分区：
文献类型：
--
作者：
Li, MX;Georgakopoulos, D;Wang, YB
背景-越来越多的证据表明心力衰竭的发生与应激反应炎性细胞因子的激活有关，包括肿瘤坏死因子- α和白细胞介素-6。然而，心肌细胞对心力衰竭的诱导作用和应激心肌的潜在调节机制仍不清楚。方法和结果-在培养的心肌细胞中，上游激活剂MKK6bE特异性激活应激激活的丝裂原激活蛋白激酶p38，可显著诱导肿瘤坏死因子- α和白细胞介素-6的分泌，而选择性p38抑制剂（SB239068）可显著阻断心肌细胞的细胞因子分泌，并增加其细胞内积累。MKK6bE在转基因心脏中的靶向表达也导致血浆肿瘤坏死因子- α和白细胞介素-6的显著升高；口服SB239068可显著降低它们的血浆水平，但增加这两种细胞因子在心脏内的积累。MKK6bE转基因心脏出现明显的间质纤维化，基质金属蛋白酶丰度增加，基质金属蛋白酶-1组织抑制剂选择性诱导；这种细胞外基质重塑也因p38抑制而显著减弱。随着细胞因子诱导和细胞外重塑，MKK6bE转基因动物表现出血流动力学功能受损，而p38抑制改善了心脏功能并延长了动物的生存期。结论：应激激活的p38激酶是心肌细胞炎症反应的关键调节因子，对应激心肌的病理重塑有重要贡献。抑制p38可能是改善心脏病理和心力衰竭演变的一种有用的治疗途径。
Background - Increasing evidence suggests that development of heart failure involves activation of stress-response inflammatory cytokines, including tumor necrosis factor-alpha and interleukin-6. Yet, the myocyte contribution to their induction in failing hearts and the underlying regulatory mechanism in stressed myocardium remain unclear.Methods and Results - In cultured cardiac myocytes, specific activation of stress-activated mitogen-activated protein kinase, p38, by upstream activator MKK6bE led to significant induction of tumor necrosis factor-alpha and interleukin-6 secretion, whereas treating cells with a selective p38 inhibitor (SB239068) significantly blocked the cytokine secretion from myocytes and increased their intracellular accumulation. Targeted expression of MKK6bE in transgenic hearts also resulted in a marked elevation in plasma tumor necrosis factor-alpha and interleukin-6; oral administration of SB239068 resulted in a significant reduction in their plasma levels but an increase in intracardiac accumulation of both cytokines. MKK6bE transgenic hearts developed marked interstitial fibrosis with increased matrix metalloproteinase abundance and selective induction of tissue inhibitor of matrix metalloproteinase-1; this extracellular matrix remodeling was also significantly attenuated by p38 inhibition. Along with cytokine induction and extracellular remodeling, MKK6bE transgenic animals displayed impaired hemodynamic function, whereas p38 inhibition improved the cardiac performance and prolonged the survival of the animals.Conclusions - Stress-activated p38 kinase is a critical regulator of inflammatory response in cardiomyocytes with significant contribution to pathological remodeling in stressed myocardium. Inhibition of p38 may represent a useful therapeutic avenue to ameliorate cardiac pathology and heart failure evolution.