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


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.


CONCLUSIONS
TSP-2 has a protective role against cardiac inflammation, injury, and dysfunction in acute viral myocarditis.
Department of Cardiology, Center for Heart Failure Research,  CARIM, Maastricht University,  The Netherlands.
Anna-Pia
AP
Papageorgiou
Melissa
M
Swinnen
Davy
D
Vanhoutte
Thierry
T
VandenDriessche
Marinee
M
Chuah
Diana
D
Lindner
Wouter
W
Verhesen
Bart
B
de Vries
Jan
J
D'hooge
Esther
E
Lutgens
Dirk
D
Westermann
Peter
P
Carmeliet
Stephane
S
Heymans
D000818:Animals; D060908:CTLA-4 Antigen / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D029822:Enterovirus B, Human / Q000472:pathogenicity*; D005355:Fibrosis; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D009200:Myocardial Contraction; D009205:Myocarditis / Q000000981:diagnostic imaging / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D009336:Necrosis; D012333:RNA, Messenger / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D019699:Thrombospondins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D016277:Ventricular Function, Left; D000099262:Thrombospondin 2
D060908:CTLA-4 Antigen; D051858:Forkhead Transcription Factors; D012333:RNA, Messenger; D019699:Thrombospondins; D000099262:Thrombospondin 2; C498833:Foxp3 protein, mouse