Document Detail


Myocardial knockdown of mRNA-stabilizing protein HuR attenuates post-MI inflammatory response and left ventricular dysfunction in IL-10-null mice.
MedLine Citation:
PMID:  20219984     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Prasanna Krishnamurthy; Erin Lambers; Suresh Verma; Tina Thorne; Gangjian Qin; Douglas W Losordo; Raj Kishore
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-03-10
Journal Detail:
Title:  FASEB journal : official publication of the Federation of American Societies for Experimental Biology     Volume:  24     ISSN:  1530-6860     ISO Abbreviation:  FASEB J.     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-07-01     Completed Date:  2010-08-03     Revised Date:  2013-05-30    
Medline Journal Info:
Nlm Unique ID:  8804484     Medline TA:  FASEB J     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2484-94     Citation Subset:  IM    
Affiliation:
Feinberg Cardiovascular Research Institute, Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA. p-krishnamurthy@northwestern.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigens, Surface / genetics*,  physiology
Cell Line
Inflammation / etiology,  prevention & control*
Interleukin-10 / deficiency*,  physiology
Macrophages
Mice
Mice, Knockout
Myocardial Infarction / pathology*
Myocardium / metabolism,  pathology*
RNA Stability
RNA, Small Interfering / pharmacology
RNA-Binding Proteins / genetics*,  physiology
Ventricular Dysfunction, Left / prevention & control*
Grant Support
ID/Acronym/Agency:
AA014575/AA/NIAAA NIH HHS; HL091983/HL/NHLBI NIH HHS; R01 HL053354-08/HL/NHLBI NIH HHS; R01 HL053354-09/HL/NHLBI NIH HHS; R01 HL053354-10/HL/NHLBI NIH HHS; R01 HL053354-11A2/HL/NHLBI NIH HHS; R01 HL053354-12/HL/NHLBI NIH HHS; R01 HL080137-01A1/HL/NHLBI NIH HHS; R01 HL080137-02/HL/NHLBI NIH HHS; R01 HL080137-03/HL/NHLBI NIH HHS; R01 HL080137-04/HL/NHLBI NIH HHS; R01 HL080137-05/HL/NHLBI NIH HHS; R01 HL091983-01A1/HL/NHLBI NIH HHS; R01 HL091983-03/HL/NHLBI NIH HHS; R01 HL091983-04/HL/NHLBI NIH HHS; R01 HL093439-02/HL/NHLBI NIH HHS; R01 HL095874-01/HL/NHLBI NIH HHS; R01 HL095874-02/HL/NHLBI NIH HHS; R01 HL095874-03/HL/NHLBI NIH HHS; R01 HL095874-04/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Antigens, Surface; 0/ELAVL1 protein, human; 0/RNA, Small Interfering; 0/RNA-Binding Proteins; 130068-27-8/Interleukin-10
Comments/Corrections

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