Systemic Inhibition of Angiopoietin-2 Prevents Endothelial Activation, and Acute Rejection in Rat Cardiac Allografts

• Published in: The Journal of heart and lung transplantation Vol. 32; no. 4; p. S136
• Main Authors: Syrjälä, S.O, Dashkevich, A, Nykänen, A.I, Leow, C.C, Alitalo, K, Lemström, K.B
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.04.2013
• Subjects: Surgery
• ISSN: 1053-2498; 1557-3117
• DOI: 10.1016/j.healun.2013.01.304

Purpose Angiopoietin-2 (Ang2) is vascular growth factor promoting vascular instability and inflammation. In our previous study, heart-targeted Ang2-inhibition prevented ischemia-reperfusion injury (IRI). Ang2 production and release, however, continues after the acute phase of IRI, and activates endothelium to attract inflammatory cells. We investigated in allogeneic rat cardiac transplantation (Tx) model the effects of preop and postop systemic recipient treatment with anti-Ang2 antibody (Ab). Methods and Materials DA donor hearts were preserved in +4 °C PBS for 4h and then transplanted to fully MHC-mismatched WF recipient rats. The recipients received anti-Ang2 Ab or control-IgG i.p. 4h prior to the Tx and, in survival studies, consecutive doses on days 1, 3, and 5. We analyzed IRI-induced endothelial activation, myocardial damage and inflammation at 6h after the Tx. In survival experiments, the recipients received additional mild CyA (1mg/kg/d) and allograft survival was evaluated by daily palpation. Results The preop recipient anti-Ang2 Ab treatment reduced IRI-induced myocardial damage, microvascular VCAM1 and ICAM1 expression, and inflammatory cell influx at 6h after the Tx. Furthermore, when the anti-Ang2 Ab treatment was continued on days 1, 3, and 5 after the Tx, the allograft survival was significantly prolonged, while single preop treatment dose failed to prolong the survival. [ figure 1 ] Conclusions In conclusion, we show that systemic recipient treatment with anti-Ang2 Ab reduces endothelial activation, inflammatory cell influx, myocardial injury, and when continued after the Tx, prolongs allograft survival. These results suggest that Ang2 is important in IRI, but also in sustaining inflammation after IRI.