Home LiteratureArticle Details
PMID: 19096025 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

IL-10 inhibits inflammation and attenuates left ventricular remodeling after myocardial infarction via activation of STAT3 and suppression of HuR.

Circulation research ·Vol. 104 ·No. 2 ·2009-01-30 ·Pages e9-18

Krishnamurthy P, Rajasingh J, Lambers E, Qin G, Losordo DW, Kishore R

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.

MeSH Terms
Animals Anti-Inflammatory Agents/administration & dosage,metabolism Antigens, Surface/genetics,metabolism Apoptosis Arterioles/metabolism Capillaries/metabolism Disease Models, Animal ELAV Proteins ELAV-Like Protein 1 Fibrosis Inflammation/metabolism,physiopathology,prevention & control Inflammation Mediators/metabolism Interleukin-10/administration & dosage,metabolism Matrix Metalloproteinase 9/genetics,metabolism Mice Mice, Inbred C57BL Myocardial Infarction/metabolism,pathology,physiopathology Myocardium/metabolism,pathology NIH 3T3 Cells Neovascularization, Physiologic Phosphorylation RNA Interference RNA, Messenger/metabolism RNA, Small Interfering/metabolism RNA-Binding Proteins/genetics,metabolism Recombinant Proteins/metabolism STAT3 Transcription Factor/metabolism Time Factors Vascular Endothelial Growth Factor A/metabolism Ventricular Function, Left/drug effects Ventricular Remodeling/drug effects p38 Mitogen-Activated Protein Kinases/metabolism
Chemicals
Anti-Inflammatory Agents Antigens, Surface ELAV Proteins ELAV-Like Protein 1 ELAVL1 protein, human Inflammation Mediators RNA, Messenger RNA, Small Interfering RNA-Binding Proteins Recombinant Proteins STAT3 Transcription Factor Stat3 protein, mouse VEGFA protein, human Vascular Endothelial Growth Factor A Interleukin-10 p38 Mitogen-Activated Protein Kinases Matrix Metalloproteinase 9 Mmp9 protein, mouse
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Krishnamurthy Prasanna
Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago IL 60611, USA.
Rajasingh Johnson
Lambers Erin
Qin Gangjian
Losordo Douglas W
Kishore Raj
References (43)
43 references, click to expand
  1. Selective matrix metalloproteinase inhibition reduces left ventricular remodeling but does not inhibit angiogenesis after myocardial infarction.
    Circulation. 2002 Feb 12;105(6):753-8 PMID: 11839633
  2. Cardiomyocyte-restricted knockout of STAT3 results in higher sensitivity to inflammation, cardiac fibrosis, and heart failure with advanced age.
    Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12929-34 PMID: 14566054
  3. Matrix metalloproteinases/tissue inhibitors of metalloproteinases: relationship between changes in proteolytic determinants of matrix composition and structural, functional, and clinical manifestations of hypertensive heart disease.
    Circulation. 2006 May 2;113(17):2089-96 PMID: 16636176
  4. Selective inhibition of p38alpha MAPK improves cardiac function and reduces myocardial apoptosis in rat model of myocardial injury.
    Am J Physiol Heart Circ Physiol. 2006 Oct;291(4):H1972-7 PMID: 16751295
  5. Activation of p38 mitogen-activated protein kinase contributes to the early cardiodepressant action of tumor necrosis factor.
    J Am Coll Cardiol. 2006 Aug 1;48(3):545-55 PMID: 16875982
  6. Matrix metalloproteinase-9 gene deletion facilitates angiogenesis after myocardial infarction.
    Am J Physiol Heart Circ Physiol. 2006 Jan;290(1):H232-9 PMID: 16126817
  7. The time course of tumor necrosis factor-alpha, inducible nitric oxide synthase and vascular endothelial growth factor expression in an experimental model of chronic myocardial infarction in rats.
    J Vasc Res. 2001 May-Jun;38(3):288-300 PMID: 11399901
  8. Inflammation and chronic heart failure-potential therapeutic role of intravenous immunoglobulin.
    Autoimmun Rev. 2004 Mar;3(3):221-7 PMID: 15110235
  9. Reduction of inflammatory cytokine expression and oxidative damage by erythropoietin in chronic heart failure.
    Cardiovasc Res. 2006 Sep 1;71(4):684-94 PMID: 16828072
  10. Differential expression of MMPs and TIMPs in moderate and severe heart failure in a transgenic model.
    J Card Fail. 2006 May;12(4):314-25 PMID: 16679266
  11. Cell cycle regulator E2F1 modulates angiogenesis via p53-dependent transcriptional control of VEGF.
    Proc Natl Acad Sci U S A. 2006 Jul 18;103(29):11015-20 PMID: 16835303
  12. Cytokine gene expression after myocardial infarction in rat hearts: possible implication in left ventricular remodeling.
    Circulation. 1998 Jul 14;98(2):149-56 PMID: 9679721
  13. Functional improvement in heart failure patients treated with beta-blockers is associated with a decline of cytokine levels.
    Int J Cardiol. 2005 Aug 18;103(2):182-6 PMID: 16080978
  14. Cytokines regulate matrix metalloproteinases and migration in cardiac fibroblasts.
    Biochem Biophys Res Commun. 2007 Oct 12;362(1):200-205 PMID: 17706606
  15. IL-10 is induced in the reperfused myocardium and may modulate the reaction to injury.
    J Immunol. 2000 Sep 1;165(5):2798-808 PMID: 10946312
  16. Negative inotropic effects of tumour necrosis factor-alpha and interleukin-1beta are ameliorated by alfentanil in rat ventricular myocytes.
    Br J Pharmacol. 2007 Mar;150(6):720-6 PMID: 17279089
  17. Signal transducer and activator of transcription 3 is required for myocardial capillary growth, control of interstitial matrix deposition, and heart protection from ischemic injury.
    Circ Res. 2004 Jul 23;95(2):187-95 PMID: 15192020
  18. Deficiency of beta1 integrins results in increased myocardial dysfunction after myocardial infarction.
    Heart. 2006 Sep;92(9):1309-15 PMID: 16547211
  19. Matrix metalloproteinases generate angiostatin: effects on neovascularization.
    J Immunol. 1998 Dec 15;161(12):6845-52 PMID: 9862716
  20. p38 mitogen activated protein kinase mediates both death signaling and functional depression in the heart.
    Ann Thorac Surg. 2005 Dec;80(6):2235-41 PMID: 16305880
  21. Overexpression of interleukin-1 receptor antagonist provides cardioprotection against ischemia-reperfusion injury associated with reduction in apoptosis.
    Circulation. 2001 Sep 18;104(12 Suppl 1):I308-I3 PMID: 11568074
  22. Toll-like receptor 4 mediates maladaptive left ventricular remodeling and impairs cardiac function after myocardial infarction.
    Circ Res. 2008 Feb 1;102(2):257-64 PMID: 18007026
  23. Temporal changes in matrix metalloproteinase expression and inflammatory response associated with cardiac rupture after myocardial infarction in mice.
    Life Sci. 2004 Feb 6;74(12):1561-72 PMID: 14729404
  24. Essential role of Smad3 in infarct healing and in the pathogenesis of cardiac remodeling.
    Circulation. 2007 Nov 6;116(19):2127-38 PMID: 17967775
  25. Differential functions of tumor necrosis factor receptor 1 and 2 signaling in ischemia-mediated arteriogenesis and angiogenesis.
    Am J Pathol. 2006 Nov;169(5):1886-98 PMID: 17071609
  26. Modulation of cytokine-induced cardiac myocyte apoptosis by nitric oxide, Bak, and Bcl-x.
    Circ Res. 1999 Jan 8-22;84(1):21-33 PMID: 9915771
  27. Endothelial progenitor cells are rapidly recruited to myocardium and mediate protective effect of ischemic preconditioning via "imported" nitric oxide synthase activity.
    Circulation. 2005 Mar 8;111(9):1114-20 PMID: 15723985
  28. Echocardiographic parameters discriminating myocardial infarction with pulmonary congestion from myocardial infarction without congestion in the mouse.
    J Appl Physiol (1985). 2005 Feb;98(2):680-9 PMID: 15475595
  29. Acute myocardial infarction induced increases in plasma tumor necrosis factor-alpha and interleukin-10 are associated with the activation of poly(ADP-ribose) polymerase of circulating mononuclear cell.
    Int J Cardiol. 2008 Jan 24;123(3):366-8 PMID: 17689746
  30. Tumor necrosis factor-alpha mediates cardiac remodeling and ventricular dysfunction after pressure overload state.
    Circulation. 2007 Mar 20;115(11):1398-407 PMID: 17353445
  31. Interleukin-10 from transplanted bone marrow mononuclear cells contributes to cardiac protection after myocardial infarction.
    Circ Res. 2008 Jul 18;103(2):203-11 PMID: 18566343
  32. ATP potentiates interleukin-1 beta-induced MMP-9 expression in mesangial cells via recruitment of the ELAV protein HuR.
    J Biol Chem. 2003 Dec 19;278(51):51758-69 PMID: 14523003
  33. Interleukin-10 therapy--review of a new approach.
    Pharmacol Rev. 2003 Jun;55(2):241-69 PMID: 12773629
  34. Targeted deletion or pharmacological inhibition of MMP-2 prevents cardiac rupture after myocardial infarction in mice.
    J Clin Invest. 2005 Mar;115(3):599-609 PMID: 15711638
  35. Targeting the inflammatory response in healing myocardial infarcts.
    Curr Med Chem. 2006;13(16):1877-93 PMID: 16842199
  36. Excessive tumor necrosis factor activation after infarction contributes to susceptibility of myocardial rupture and left ventricular dysfunction.
    Circulation. 2004 Nov 16;110(20):3221-8 PMID: 15533863
  37. Tumor necrosis factor-alpha receptor p75 is required in ischemia-induced neovascularization.
    Circulation. 2007 Feb 13;115(6):752-62 PMID: 17261656
  38. CD44 is critically involved in infarct healing by regulating the inflammatory and fibrotic response.
    J Immunol. 2008 Feb 15;180(4):2625-33 PMID: 18250474
  39. Inhibition of NFkappaB activation with curcumin attenuates plasma inflammatory cytokines surge and cardiomyocytic apoptosis following cardiac ischemia/reperfusion.
    J Surg Res. 2005 May 1;125(1):109-16 PMID: 15836859
  40. IL-10-induced TNF-alpha mRNA destabilization is mediated via IL-10 suppression of p38 MAP kinase activation and inhibition of HuR expression.
    FASEB J. 2006 Oct;20(12):2112-4 PMID: 16935932
  41. Tumor necrosis factor receptors 1 and 2 differentially regulate survival, cardiac dysfunction, and remodeling in transgenic mice with tumor necrosis factor-alpha-induced cardiomyopathy.
    Circulation. 2004 Apr 20;109(15):1892-7 PMID: 15051641
  42. The role of the chemokines in myocardial ischemia and reperfusion.
    Curr Vasc Pharmacol. 2004 Apr;2(2):163-74 PMID: 15320517
  43. Cellular basis for the acute inhibitory effects of IL-6 and TNF- alpha on excitation-contraction coupling.
    J Mol Cell Cardiol. 1999 Aug;31(8):1457-67 PMID: 10423344
Article Info
Journal
Circulation research
Abbr.
Circ Res
ISSN
1524-4571
DOI
10.1161/CIRCRESAHA.108.188243
Published
2009-01-30
Epub
2008-00-18
Pages
e9-18
Language
English
Region
United States
NLM ID
0047103
PMCID
PMC2774810
Subset
IM
Grants
NHLBI NIH HHS · R01 HL091983 · United States
NIAAA NIH HHS · AA014575 · United States
NIAAA NIH HHS · R21 AA014575 · United States
NIAAA NIH HHS · R21 AA014575-01A2 · United States
NHLBI NIH HHS · R01 HL091983-01A1 · United States
External Links
PubMed source DOI: 10.1161/CIRCRESAHA.108.188243 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2