Myocardial knockdown of mRNA-stabilizing protein HuR attenuates post-MI inflammatory response and left ventricular dysfunction in IL-10-null mice
Myocardial knockdown of mRNA-stabilizing protein HuR attenuates post-MI inflammatory response and left ventricular dysfunction in IL-10-null mice
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DOI：
10.1096/fj.09-149815
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发表时间：
2010-07-01
期刊：
影响因子：
4.8
通讯作者：
Kishore, Raj
中科院分区：
文献类型：
--
作者：
Krishnamurthy, Prasanna;Lambers, Erin;Kishore, Raj
心肌梗死（MI）后持续的炎症反应与左心室（LV）功能障碍和不良重构相关。IL-10通过抑制HuR介导的促炎细胞因子的mRNA稳定来抑制炎症。在这里，我们报告了MI后，IL-10（-/-）小鼠表现出严重的LV功能障碍、纤维化和心肌细胞凋亡。短发夹RNA（shRNA）介导的心肌HuR敲低可显著逆转MI诱导的左室功能障碍和左室重塑。HuR敲低显著降低MI诱导的心肌细胞凋亡，同时降低p53表达。此外，HuR敲低显著减少了梗死面积和纤维化面积，这反过来又与TGF-β表达减少有关。在体外，小鼠巨噬细胞系RAW 264.7中HuR的稳定敲低证实了体内数据，并揭示了LPS攻击后TNF-α、TGF-β和p53的mRNA表达降低，这与这些基因的mRNA稳定性显著降低有关。总之，我们的研究表明HuR是IL-10的直接靶点，HuR敲低模拟IL-10的抗炎作用。克里希纳穆尔蒂，P.，Lambers，E.，维尔玛，S.，索恩，T.，Qin，G.，Losordo，D. W.，基肖尔河心肌敲低mRNA稳定蛋白HuR可减轻IL-10缺失小鼠心肌梗死后炎症反应和左心室功能障碍FASEB J.24，2484-2494（2010）。www.fasebj.org
Prolonged inflammatory response is associated with left ventricular (LV) dysfunction and adverse remodeling following myocardial infarction (MI). IL-10 inhibits inflammation by suppressing HuR-mediated mRNA stabilization of proinflammatory cytokines. Here we report that following MI, IL-10(-/-) mice showed exaggerated LV dysfunction, fibrosis, and cardiomyocyte apoptosis. Short-hairpin RNA (shRNA)-mediated knockdown of HuR in the myocardium significantly reversed MI-induced LV dysfunctions and LV remodeling. HuR knockdown significantly reduced MI-induced cardiomyocyte apoptosis concomitant with reduced p53 expression. Moreover, HuR knockdown significantly reduced infarct size and fibrosis area, which in turn was associated with decreased TGF-beta expression. In vitro, stable knockdown of HuR in mouse macrophage cell line RAW 264.7 corroborated in vivo data and revealed reduced mRNA expression of TNF-alpha, TGF-beta, and p53 following LPS challenge, which was associated with a marked reduction in the mRNA stability of these genes. Taken together, our studies suggest that HuR is a direct target of IL-10, and HuR knockdown mimics anti-inflammatory effects of IL10.-Krishnamurthy, P., Lambers, E., Verma, S., Thorne, T., Qin, G., Losordo, D. W., Kishore, R. Myocardial knockdown of mRNA-stabilizing protein HuR attenuates post-MI inflammatory response and left ventricular dysfunction in IL-10-null mice. FASEB J. 24, 2484-2494 (2010). www.fasebj.org