Abstract 310: Thrombospondin 2 Protects Against Uncontrolled Cardiac Inflammation and Injury During Viral Myocarditis

Abstract

Background-The matricellular protein thrombospondin 2 (TSP2), a secreted extracellular matrix (ECM) glycoprotein, plays a crucial role in controlling cell-matrix interaction in tissue repair and cancer biology. Our previous data revealed that increased TSP2 reinforces the matrix and protects the against heart failure during hypertension. The present study investigated whether TSP2 may protects against exaggerated cardiac inflammation, injury and dysfunction during viral myocarditis. Methods and Results-Therefore, mortality, cardiac inflammation and function were investigated in TSP2-null (KO) and wild type (WT) mice, and after adeno-associated virus (AAV)-9 mediated TSP-2 overexpression in WT, in a mouse model of coxsackievirus B3 (CVB3)-induced (106 CCID50 ip CBV3, 14 days) myocarditis. Absence of TSP2 resulted in an increased mortality in TSP2-null as compared with WT mice in both viral myocarditis (KO: 37,5% vs WT: 0%; n=8 per group). Histological analysis revealed increased cardiac inflammation (60 % increase of CD3-positive T-lymphocytes), necrosis and injury in TSP2-null compared to WT mice at 14 days of viral myocarditis. Ultrastructural analysis showed increased inflammation, matrix disruption and myocyte injury in absence of TSP2, together resulting in depressed systolic function (% FS; 40.1 ± 2.3 in WT vs. 24.6 ± 1.7 in KO mice, P<0.05) and increased cardiac dilatation (end-diastolic dimensions, mm; 2.6 ± 0.18 in WT vs. 3.6 ± 0.06 in KO mice, P<0.05) at 14 days at echocardiography. In concordance, AAV9-gene transfer of TSP2, with 50 % increase in cardiac TSP-2 expression, significantly reduced cardiac inflammation (60% reduction) and injury at 14 days as compared to control AAV9-GFP. Conclusion-Together, these data clearly point towards a novel protective role for TSP2 against uncontrolled inflammation, myocardial injury and dysfunction in acute viral myocarditis.