Myocardial knockdown of mRNA-stabilizing protein HuR attenuates post-MI inflammatory response and left ventricular dysfunction in IL-10-null mice.
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.
Krishnamurthy
Prasanna
P
Feinberg Cardiovascular Research Institute, Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA. p-krishnamurthy@northwestern.edu
Lambers
Erin
E
Verma
Suresh
S
Thorne
Tina
T
Qin
Gangjian
G
Losordo
Douglas W
DW
Kishore
Raj
R
D000818:Animals; D000954:Antigens, Surface / Q000235:genetics* / Q000502:physiology; D002460:Cell Line; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D007249:Inflammation / Q000209:etiology / Q000517:prevention & control*; D016753:Interleukin-10 / Q000172:deficiency* / Q000502:physiology; D008264:Macrophages; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D020871:RNA Stability; D034741:RNA, Small Interfering / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D018487:Ventricular Dysfunction, Left / Q000517:prevention & control*
D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D016753:Interleukin-10