Critical role of endogenous thrombospondin-1 in preventing expansion of healing myocardial infarcts

Nikolaos G. Frangogiannis, Guofeng Ren, Oliver Dewald, Pawel Zymek, Sandra Haudek, Anna Koerting, Kim Winkelmann, Lloyd H. Michael, Jack Lawler, Mark L. Entman

Research output: Contribution to journalArticle

213 Citations (Scopus)

Abstract

Background - Matricellular proteins are extracellular matrix proteins that do not contribute directly to tissue integrity but are capable of modulating cell function. We hypothesized that the matricellular protein thrombospondin (TSP)-1, a potent inhibitor of angiogenesis and activator of transforming growth factor (TGF-β), is induced in healing myocardial infarcts and plays a role in suppressing the postinfarction inflammatory response, inhibiting local angiogenesis, and limiting expansion of granulation tissue into the noninfarcted area. Methods and Results - We used a canine and a murine model of reperfused infarction. TSP-1 mRNA was induced in canine infarcts after 1 hour of ischemia and 3 to 7 days of reperfusion. TSP-1 protein showed a strikingly selective localization in the extracellular matrix, microvascular endothelium, and a subset of mononuclear cells of the infarct border zone after 5 to 28 days of reperfusion. Isolated canine venous endothelial cells showed low-level constitutive expression of TSP-1 mRNA, which was markedly induced by TGF-β, and basic fibroblast growth factor. Murine infarcts also had marked TSP-1 deposition in the border zone. Infarcted TSP-1-/- mice exhibited sustained upregulation of the chemokines monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, and interferon-γ-inducible protein-10/CXCL10 and the cytokines interleukin-1β, interleukin-6, and TGF-β, suggesting an enhanced and prolonged postinfarction inflammatory response. In addition, TSP-1-/- mice had markedly increased macrophage and myofibroblast density in infarcts and in remodeling noninfarcted myocardial areas neighboring the myocardial scar, suggesting expansion of granulation tissue formation into the noninfarcted territory. TSP-1 -/- animals had more extensive postinfarction remodeling than wild-type mice, although infarct size was similar in both groups. Conclusions - The infarct border zone may be capable of modulating the healing process through its unique extracellular matrix content. The selective endogenous expression of TSP-1 in the infarct border zone may serve as a "barrier," limiting expansion of granulation tissue and protecting the noninfarcted myocardium from fibrotic remodeling.

Original languageEnglish (US)
Pages (from-to)2935-2942
Number of pages8
JournalCirculation
Volume111
Issue number22
DOIs
StatePublished - Jun 7 2005
Externally publishedYes

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Thrombospondin 1
Myocardial Infarction
Granulation Tissue
Transforming Growth Factors
Canidae
Reperfusion
Extracellular Matrix
Chemokine CXCL10
Macrophage Inflammatory Proteins
Messenger RNA
Proteins
Angiogenesis Inhibitors
Myofibroblasts
Chemokine CCL2
Extracellular Matrix Proteins
Fibroblast Growth Factor 2
Interleukin-1
Chemokines
Infarction
Endothelium

Keywords

  • Extracellular matrix
  • Immunology
  • Inflammation
  • Myocardial infarction
  • Pathology

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Critical role of endogenous thrombospondin-1 in preventing expansion of healing myocardial infarcts. / Frangogiannis, Nikolaos G.; Ren, Guofeng; Dewald, Oliver; Zymek, Pawel; Haudek, Sandra; Koerting, Anna; Winkelmann, Kim; Michael, Lloyd H.; Lawler, Jack; Entman, Mark L.

In: Circulation, Vol. 111, No. 22, 07.06.2005, p. 2935-2942.

Research output: Contribution to journalArticle

Frangogiannis, NG, Ren, G, Dewald, O, Zymek, P, Haudek, S, Koerting, A, Winkelmann, K, Michael, LH, Lawler, J & Entman, ML 2005, 'Critical role of endogenous thrombospondin-1 in preventing expansion of healing myocardial infarcts', Circulation, vol. 111, no. 22, pp. 2935-2942. https://doi.org/10.1161/CIRCULATIONAHA.104.510354
Frangogiannis, Nikolaos G. ; Ren, Guofeng ; Dewald, Oliver ; Zymek, Pawel ; Haudek, Sandra ; Koerting, Anna ; Winkelmann, Kim ; Michael, Lloyd H. ; Lawler, Jack ; Entman, Mark L. / Critical role of endogenous thrombospondin-1 in preventing expansion of healing myocardial infarcts. In: Circulation. 2005 ; Vol. 111, No. 22. pp. 2935-2942.
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T1 - Critical role of endogenous thrombospondin-1 in preventing expansion of healing myocardial infarcts

AU - Frangogiannis, Nikolaos G.

AU - Ren, Guofeng

AU - Dewald, Oliver

AU - Zymek, Pawel

AU - Haudek, Sandra

AU - Koerting, Anna

AU - Winkelmann, Kim

AU - Michael, Lloyd H.

AU - Lawler, Jack

AU - Entman, Mark L.

PY - 2005/6/7

Y1 - 2005/6/7

N2 - Background - Matricellular proteins are extracellular matrix proteins that do not contribute directly to tissue integrity but are capable of modulating cell function. We hypothesized that the matricellular protein thrombospondin (TSP)-1, a potent inhibitor of angiogenesis and activator of transforming growth factor (TGF-β), is induced in healing myocardial infarcts and plays a role in suppressing the postinfarction inflammatory response, inhibiting local angiogenesis, and limiting expansion of granulation tissue into the noninfarcted area. Methods and Results - We used a canine and a murine model of reperfused infarction. TSP-1 mRNA was induced in canine infarcts after 1 hour of ischemia and 3 to 7 days of reperfusion. TSP-1 protein showed a strikingly selective localization in the extracellular matrix, microvascular endothelium, and a subset of mononuclear cells of the infarct border zone after 5 to 28 days of reperfusion. Isolated canine venous endothelial cells showed low-level constitutive expression of TSP-1 mRNA, which was markedly induced by TGF-β, and basic fibroblast growth factor. Murine infarcts also had marked TSP-1 deposition in the border zone. Infarcted TSP-1-/- mice exhibited sustained upregulation of the chemokines monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, and interferon-γ-inducible protein-10/CXCL10 and the cytokines interleukin-1β, interleukin-6, and TGF-β, suggesting an enhanced and prolonged postinfarction inflammatory response. In addition, TSP-1-/- mice had markedly increased macrophage and myofibroblast density in infarcts and in remodeling noninfarcted myocardial areas neighboring the myocardial scar, suggesting expansion of granulation tissue formation into the noninfarcted territory. TSP-1 -/- animals had more extensive postinfarction remodeling than wild-type mice, although infarct size was similar in both groups. Conclusions - The infarct border zone may be capable of modulating the healing process through its unique extracellular matrix content. The selective endogenous expression of TSP-1 in the infarct border zone may serve as a "barrier," limiting expansion of granulation tissue and protecting the noninfarcted myocardium from fibrotic remodeling.

AB - Background - Matricellular proteins are extracellular matrix proteins that do not contribute directly to tissue integrity but are capable of modulating cell function. We hypothesized that the matricellular protein thrombospondin (TSP)-1, a potent inhibitor of angiogenesis and activator of transforming growth factor (TGF-β), is induced in healing myocardial infarcts and plays a role in suppressing the postinfarction inflammatory response, inhibiting local angiogenesis, and limiting expansion of granulation tissue into the noninfarcted area. Methods and Results - We used a canine and a murine model of reperfused infarction. TSP-1 mRNA was induced in canine infarcts after 1 hour of ischemia and 3 to 7 days of reperfusion. TSP-1 protein showed a strikingly selective localization in the extracellular matrix, microvascular endothelium, and a subset of mononuclear cells of the infarct border zone after 5 to 28 days of reperfusion. Isolated canine venous endothelial cells showed low-level constitutive expression of TSP-1 mRNA, which was markedly induced by TGF-β, and basic fibroblast growth factor. Murine infarcts also had marked TSP-1 deposition in the border zone. Infarcted TSP-1-/- mice exhibited sustained upregulation of the chemokines monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, and interferon-γ-inducible protein-10/CXCL10 and the cytokines interleukin-1β, interleukin-6, and TGF-β, suggesting an enhanced and prolonged postinfarction inflammatory response. In addition, TSP-1-/- mice had markedly increased macrophage and myofibroblast density in infarcts and in remodeling noninfarcted myocardial areas neighboring the myocardial scar, suggesting expansion of granulation tissue formation into the noninfarcted territory. TSP-1 -/- animals had more extensive postinfarction remodeling than wild-type mice, although infarct size was similar in both groups. Conclusions - The infarct border zone may be capable of modulating the healing process through its unique extracellular matrix content. The selective endogenous expression of TSP-1 in the infarct border zone may serve as a "barrier," limiting expansion of granulation tissue and protecting the noninfarcted myocardium from fibrotic remodeling.

KW - Extracellular matrix

KW - Immunology

KW - Inflammation

KW - Myocardial infarction

KW - Pathology

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