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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents / administration & dosage
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Anti-Inflammatory Agents / metabolism*
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Antigens, Surface / genetics
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Antigens, Surface / metabolism*
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Apoptosis
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Arterioles / metabolism
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Capillaries / metabolism
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Disease Models, Animal
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ELAV Proteins
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ELAV-Like Protein 1
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Fibrosis
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Inflammation / metabolism
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Inflammation / physiopathology
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Inflammation / prevention & control*
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Inflammation Mediators / metabolism
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Interleukin-10 / administration & dosage
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Interleukin-10 / metabolism*
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Matrix Metalloproteinase 9 / genetics
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Matrix Metalloproteinase 9 / metabolism
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Mice
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Mice, Inbred C57BL
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Myocardial Infarction / metabolism*
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Myocardial Infarction / pathology
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Myocardial Infarction / physiopathology
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Myocardium / metabolism*
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Myocardium / pathology
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NIH 3T3 Cells
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Neovascularization, Physiologic
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Phosphorylation
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RNA Interference
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RNA, Messenger / metabolism
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RNA, Small Interfering / metabolism
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / metabolism*
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Recombinant Proteins / metabolism
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STAT3 Transcription Factor / metabolism*
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Time Factors
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Vascular Endothelial Growth Factor A / metabolism
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Ventricular Function, Left* / drug effects
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Ventricular Remodeling* / drug effects
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Anti-Inflammatory Agents
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Antigens, Surface
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ELAV Proteins
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ELAV-Like Protein 1
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ELAVL1 protein, human
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Inflammation Mediators
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RNA, Messenger
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RNA, Small Interfering
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RNA-Binding Proteins
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Recombinant Proteins
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STAT3 Transcription Factor
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Stat3 protein, mouse
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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Interleukin-10
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p38 Mitogen-Activated Protein Kinases
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Matrix Metalloproteinase 9
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Mmp9 protein, mouse