TY - JOUR
T1 - Myocardial knockdown of mRNA-stabilizing protein HuR attenuates post-MI inflammatory response and left ventricular dysfunction in IL-10-null mice
AU - Krishnamurthy, Prasanna
AU - Lambers, Erin
AU - Verma, Suresh
AU - Thorne, Tina
AU - Qin, Gangjian
AU - Losordo, Douglas W.
AU - Kishore, Raj
N1 - Copyright:
Copyright 2010 Elsevier B.V., All rights reserved.
PY - 2010/7
Y1 - 2010/7
N2 - 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-β 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-α, TGF-β, 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.
AB - 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-β 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-α, TGF-β, 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.
KW - Apoptosis
KW - Cytokines
KW - Fibrosis
KW - Inflammation
KW - Myocardial infarction
UR - http://www.scopus.com/inward/record.url?scp=77954439736&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77954439736&partnerID=8YFLogxK
U2 - 10.1096/fj.09-149815
DO - 10.1096/fj.09-149815
M3 - Article
C2 - 20219984
AN - SCOPUS:77954439736
SN - 0892-6638
VL - 24
SP - 2484
EP - 2494
JO - FASEB Journal
JF - FASEB Journal
IS - 7
ER -