Intervention effect of PI3Kgamma inhibitor AS605240 on autoimmune myocarditis in mice

Objective To investigate the therapeutic effect of PI3Kγ inhibitor AS605240 on autoimmune myocarditis in mice. Methods BALB/c mice were randomly divided into three groups,AS605240 group and vehicle group were injected subcutaneously with emulsions containing CFA and 100 ng peptide which derived from murine cardiac α-myosin heavy chain on day 0 and 7 while control group were injected with emulsions containing CFA and PBS. AS605240 group received the oral administration of AS605240 50 mg/(kg·d). The vehicle group received the oral administration of an equal volume of 0.5% carboxymethylcellulose. 21 days after the first immunization,mice were sacrificed,heart and body weight were measured. Myocarditis severity was evaluated according to a semi-quantitative scoring system in heart sections. Immunohistochemistry was performed to determine the effect of AS605240 on myocardium macrophage infiltration; TNF-α levels in myocardium were determined by ELISA. In vitro and in vivo chemotaxis assays were performed to determine the effect of AS605240 on MCP-1-induced macrophage chemotaxis. Results Histological examination of the heart showed that AS605240 significantly relieved the murine myocarditis and reduced heart/body weight ratios in experimental autoimmune myocarditis (EAM) (P0.01). Immunohistochemical detection showed that AS605240 significantly suppressed macrophage infiltration into the heart with EAM. ELISA demonstrated that AS605240 down-regulated TNF-α levels in myocardium (P0.01). In vitro and in vivo chemotaxis assays indicated that AS605240 significantly suppressed MCP-1-induced macrophage chemotaxis (P0.01). Conclusion AS605240 may be an effective drug for autoimmune myocarditis,of which the mechanism is relating to suppress macrophage chemotaxis and macrophage infiltration into myocardium,and to decrease TNF-α levels in myocardium.