TNF-α Upregulates Fgl2 Expression in Rat Myocardial Ischemia/Reperfusion Injury

Objective: Proinflammatory cytokine TNF-a during MI/R injury has been studied extensively. However, how TNF-a induces microvascular dysfunction in MI/R is still unclear. This study investigates whether TNF-a regulates fibrinogen-like protein 2 (fgl2) expression, a procoagulant resulting in the formation of fibrin-rich microthrombus in MI/R injury. Methods and Results: Microthrombosis, TNF-a and fgl2 expression were assessed in rats with MI/R injury. The effect of TNF-a on fgl2 expression and fgl2 prothrombinase activity was investigated in CMECs, then CMECs were pretreated with selective inhibitors of NF-jB and p38 MAPK pathways. TNF-a and fgl2 expression were both upregulated in MI/R group. When neutralization of TNF-a, fgl2 expression was decreased in vivo. Fgl2 expression was upregulated in CMECs exposed to TNF-a. Accordingly, the ability of thrombin generation was increased in CMECs. Besides, TNF-ainduced fgl2 expression in the cells was suppressed by NF-jB inhibitor PDTC and/or p38 MAPK inhibitor SB203580. Conclusion: TNF-a upregulates fgl2 expression via activation of NF-kB and p38 MAPK in CMECs. TNF-a-induced flg2 in CMECs mediates the formation of fibrin-rich microthrombus, which may be one of the mechanisms of microvascular dysfunction or obstruction due to MI/R injury.