Feinberg Cardiovascular Research Institute, Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
FASEB J. 2010 Jul;24(7):2484-94. doi: 10.1096/fj.09-149815. Epub 2010 Mar 10.
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 IL-10.
炎症反应持续存在与心肌梗死后左心室（LV）功能障碍和不良重构有关。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，我们报告说，在心肌梗死后，IL-10（-/-）小鼠表现出 LV 功能障碍、纤维化和心肌细胞凋亡加剧。心肌中短发夹 RNA（shRNA）介导的 HuR 敲低显著逆转了 MI 诱导的 LV 功能障碍和 LV 重构。HuR 敲低显著减少了 MI 诱导的心肌细胞凋亡，同时降低了 p53 的表达。此外，HuR 敲低显著减少了梗死面积和纤维化面积，这与 TGF-β表达的降低有关。在体外，在小鼠巨噬细胞系 RAW 264.7 中稳定敲低 HuR 证实了体内数据，并显示出 LPS 刺激后 TNF-α、TGF-β 和 p53 的 mRNA 表达减少，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 的直接靶标，HuR 敲低模拟了 IL-10 的抗炎作用。
