IL-10 inhibits inflammation and attenuates left ventricular remodeling after myocardial infarction via activation of STAT3 and suppression of HuR.
IL-10 inhibits inflammation and attenuates left ventricular remodeling after myocardial infarction via activation of STAT3 and suppression of HuR.
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DOI：
10.1161/circresaha.108.188243
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发表时间：
2009-01-30
影响因子：
20.1
通讯作者：
Kishore R
中科院分区：
文献类型：
--
作者：
Krishnamurthy P;Rajasingh J;Lambers E;Qin G;Losordo DW;Kishore R
急性心肌梗死（AMI）后持续性炎症反应对左室功能和重构有不良影响。我们假设IL-10治疗抑制炎症可减轻AMI后左室功能障碍和重塑。在诱导AMI后，用生理盐水或重组IL-10处理小鼠，并评价炎症反应和LV功能和结构重构的变化。IL-10显著抑制心肌中炎性细胞的浸润和炎性细胞因子的表达。这些变化与IL-10介导的p38 MAP激酶激活抑制和细胞因子mRNA稳定蛋白HuR抑制有关。IL-10治疗显著改善了左室功能，缩小了梗死面积，减轻了梗死壁变薄。MI诱导的MMP 9表达和活性增加与纤维化增加相关，因为IL-10治疗降低了MMP 9活性和纤维化。siRNA敲除HuR模拟IL-10介导的NIH 3 T3细胞中MMP-9表达和活性的降低。此外，IL-10治疗显著增加了梗死心肌中的毛细血管密度，这与增强的STAT 3磷酸化相关。综上所述，我们的研究表明，IL-10通过抑制HuR/MMP 9抑制纤维化和通过激活STAT 3增强毛细血管密度来抑制炎症反应并有助于改善LV功能和重塑。
Persistent inflammatory response has adverse effects on left ventricular (LV) function and remodeling following acute myocardial infarction (AMI). We hypothesized that suppression of inflammation with IL-10 treatment attenuates LV dysfunction and remodeling after AMI. After the induction of AMI, mice were treated with either saline or recombinant IL-10, and inflammatory response and LV functional and structural remodeling changes were evaluated. IL-10 significantly suppressed infiltration of inflammatory cells and expression of inflammatory cytokines in the myocardium. These changes were associated with IL-10-mediated inhibition of p38 MAP kinase activation and repression of cytokine mRNA stabilizing protein, HuR. IL-10 treatment significantly improved LV functions, reduced infarct size and attenuated infarct wall thinning. MI-induced increase in MMP9 expression and activity was associated with increased fibrosis since IL-10 treatment reduced both MMP9 activity and fibrosis. siRNA knockdown of HuR mimicked IL-10 mediated reduction in MMP-9 expression and activity in NIH3T3 cells. Moreover, IL-10 treatment significantly increased capillary density in the infarcted myocardium which was associated with enhanced STAT3 phosphorylation. Taken together, our studies demonstrate that IL-10 suppresses inflammatory response and contributes to improved LV function and remodeling by inhibiting fibrosis via suppression of HuR/MMP9 and by enhancing capillary density through activation of STAT3.