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FASEB J. 2010 Jul;24(7):2484-94. doi: 10.1096/fj.09-149815. Epub 2010 Mar 10.

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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1
Feinberg Cardiovascular Research Institute, Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA. p-krishnamurthy@northwestern.edu

Abstract

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.

PMID:
20219984
PMCID:
PMC2887267
DOI:
10.1096/fj.09-149815
[Indexed for MEDLINE]
Free PMC Article

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