title: IL-10 inhibits inflammation and attenuates left ventricular remodeling after myocardial infarction via activation of STAT3 and suppression of HuR.
abstract: Persistent inflammatory response has adverse effects on left ventricular (LV) function and remodeling following acute myocardial infarction. We hypothesized that suppression of inflammation with interleukin (IL)-10 treatment attenuates LV dysfunction and remodeling after acute myocardial infarction. After the induction of acute myocardial infarction, mice were treated with either saline or recombinant IL-10, and inflammatory response and LV functional and structural remodeling changes were evaluated. IL-10 significantly suppressed infiltration of inflammatory cells and expression of proinflammatory cytokines in the myocardium. These changes were associated with IL-10-mediated inhibition of p38 mitogen-activated protein kinase activation and repression of the cytokine mRNA-stabilizing protein HuR. IL-10 treatment significantly improved LV functions, reduced infarct size, and attenuated infarct wall thinning. Myocardial infarction-induced increase in matrix metalloproteinase (MMP)-9 expression and activity was associated with increased fibrosis, whereas IL-10 treatment reduced both MMP-9 activity and fibrosis. Small interfering RNA knockdown of HuR mimicked IL-10-mediated reduction in MMP-9 expression and activity in NIH3T3 cells. Moreover, IL-10 treatment significantly increased capillary density in the infarcted myocardium which was associated with enhanced STAT3 phosphorylation. Taken together, our studies demonstrate that IL-10 suppresses inflammatory response and contributes to improved LV function and remodeling by inhibiting fibrosis via suppression of HuR/MMP-9 and by enhancing capillary density through activation of STAT3.
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago IL 60611, USA.
authors.forename: Prasanna
authors.initials: P
authors.lastname: Krishnamurthy
authors.forename: Johnson
authors.initials: J
authors.lastname: Rajasingh
authors.forename: Erin
authors.initials: E
authors.lastname: Lambers
authors.forename: Gangjian
authors.initials: G
authors.lastname: Qin
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Losordo
authors.forename: Raj
authors.initials: R
authors.lastname: Kishore
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000378:metabolism*; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D001160:Arterioles / Q000378:metabolism; D002196:Capillaries / Q000378:metabolism; D004195:Disease Models, Animal; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D005355:Fibrosis; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D016753:Interleukin-10 / Q000008:administration & dosage / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D041681:NIH 3T3 Cells; D018919:Neovascularization, Physiologic; D010766:Phosphorylation; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D018836:Inflammation Mediators; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D016753:Interleukin-10; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse