[Intervention effect of PI3Kgamma inhibitor AS605240 on autoimmune myocarditis in mice].
OBJECTIVE
To investigate the therapeutic effect of PI3Kgamma 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 alpha-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 x 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-alpha 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) (P< 0.01). Immunohistochemical detection showed that AS605240 significantly suppressed macrophage infiltration into the heart with EAM. ELISA demonstrated that AS605240 down-regulated TNF-alpha levels in myocardium (P<0.01). In vitro and in vivo chemotaxis assays indicated that AS605240 significantly suppressed MCP-1-induced macrophage chemotaxis (P<0.01).


CONCLUSIONS
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-alpha levels in myocardium.
Jin
Ke
K
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
Song
Li-Fang
LF
He
Chun-Mei
CM
Wang
Zhen-Ling
ZL
Hu
Xiao-Hong
XH
Wu
Xiao-Hua
XH
D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology; D018932:Chemokine CCL2 / Q000378:metabolism; D058544:Class Ib Phosphatidylinositol 3-Kinase; D015536:Down-Regulation / Q000187:drug effects; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009205:Myocarditis / Q000188:drug therapy* / Q000276:immunology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines / Q000627:therapeutic use*; D011897:Random Allocation; D045162:Thiazolidinediones / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
C505144:5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione; D018932:Chemokine CCL2; D007527:Isoenzymes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse