Thrombospondin-2 prevents cardiac injury and dysfunction in viral myocarditis through the activation of regulatory T-cells

Anna Pia Papageorgiou, Melissa Swinnen, Davy Vanhoutte, Thierry Vandendriessche, Marinee Chuah, Diana Lindner, Wouter Verhesen, Bart De Vries, Jan Dhooge, Esther Lutgens, Dirk Westermann, Peter Carmeliet, Stephane Heymans

Research output: Contribution to journalArticlepeer-review

Abstract

Aims: Thrombospondin-2 (TSP-2) modulates matrix integrity and myocyte survival in the hypertensive or ageing heart. Whether TSP-2 may affect cardiac inflammation and injury, in particular during acute viral myocarditis, is completely unknown. Methods and results: Therefore, mortality, cardiac inflammation, and function were assessed in TSP-2-null (KO) and wild-type (WT) mice in human Coxsackie virus B3 (CVB3)-induced myocarditis. TSP-2 KO had an increased mortality when compared with WT mice during viral myocarditis. The absence of TSP-2 resulted in increased cardiac inflammation and injury at 14 days, which resulted in depressed systolic function [fractional shortening (FS); 34 ± 2.6 in WT vs. 24 ± 1.8 in KO mice, P< 0.05] and increased cardiac dilatation (end-diastolic dimensions, mm; 3.7 ± 0.09 in WT vs. 4.8 ± 0.06 in KO mice, P< 0.05) 35 days post-infection. Lack of TSP-2 resulted in a decreased activation of the anti-inflammatory T-regulatory cells, as indicated by a lower number of CD25-positive T-cells, and significantly decreased gene expression of regulatory T-cell markers, Foxp3 and CTLA-4. Finally, overexpression of TSP-2 in WT hearts using cardiotropic vectors derived from adeno-associated virus serotype 9 (AAV9) inhibited cardiac inflammation and injury at 14 days and improved cardiac function at 35 days post-CVB3 infection when compared with control AAV9. Conclusion: TSP-2 has a protective role against cardiac inflammation, injury, and dysfunction in acute viral myocarditis. Published on behalf of the European Society of Cardiology. All rights reserved.

Original languageEnglish (US)
Pages (from-to)115-124
Number of pages10
JournalCardiovascular research
Volume94
Issue number1
DOIs
StatePublished - Apr 1 2012

Keywords

  • Inflammation
  • Matrix
  • Myocarditis
  • Regulatory T cells
  • Viruses

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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