TY - JOUR
T1 - Thrombospondin-2 prevents cardiac injury and dysfunction in viral myocarditis through the activation of regulatory T-cells
AU - Papageorgiou, Anna-Pia
AU - Swinnen, Melissa
AU - Vanhoutte, Davy
AU - VandenDriessche, Thierry
AU - Chuah, Marinee
AU - Lindner, Diana
AU - Verhesen, Wouter
AU - de Vries, Bart
AU - D'hooge, Jan
AU - Lutgens, Esther
AU - Westermann, Dirk
AU - Carmeliet, Peter
AU - Heymans, Stephane
PY - 2012/4/1
Y1 - 2012/4/1
N2 - 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. 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. TSP-2 has a protective role against cardiac inflammation, injury, and dysfunction in acute viral myocarditis.
AB - 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. 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. TSP-2 has a protective role against cardiac inflammation, injury, and dysfunction in acute viral myocarditis.
KW - Matrix
KW - Inflammation
KW - Viruses
KW - Myocarditis
KW - Regulatory T cells
U2 - 10.1093/cvr/cvs077
DO - 10.1093/cvr/cvs077
M3 - Article
C2 - 22308237
SN - 0008-6363
VL - 94
SP - 115
EP - 124
JO - Cardiovascular Research
JF - Cardiovascular Research
IS - 1
ER -