Cd80 and Cd86 Masking on Antigen-Presenting Cells Exhibited Protection From Myocardial Necrosis and Ischemia-Reperfusion Injury: A Preclinical Validation

Objective: Myocardial Ischemia due to coronary obstruction after a critical threshold level, resulting in myocardial damage as a consequence of myocardial cell death. However, reperfusion itself causes the generation of oxygen free radicals, disturbed cation homeostasis, and depletion of cellular energy due to the involvement of molecular signaling. Abatacept, a recombinant fusion protein that inhibits the activation of T-cells through binding with CD80 and CD86 receptors of antigen-presenting cells and prevents major inflammatory responses. This study identifies the anti-inflammatory potential of abatacept by minimizing the immune-cell activation, and infiltration at myocardium during injury. Design and method: This study was conducted in two parts on male Wistar rats. Firstly, abatacept was administered at 2.5, 5 & 10 mg/kg; s.c. for 21 days and evaluated in the Isoproterenol (ISO)-induced myocardial necrosis model of rats, in which ISO was injection subcutaneously on 20th and 21st day at 85 mg/kg dose, after an interval of 24 h post last ISO injection, the rat was sacrificed after hemodynamic measurement and the optimal dose of Abatacept was calculated through biochemical (oxidant-antioxidant / cardiac injury marker), histopathological and molecular investigations. Secondly, after abatacept administration at optimal dose for 21 days, the rats were anesthetized and Ischemia-Reperfusion injury was induced through LAD coronary artery ligation for 60 min and re-opening for 60 min. The effect of abatacept was based on hemodynamic, biochemical, and molecular investigation of inflammation, apoptosis, and necroptosis signaling pathway-related proteins. Results: Improved hemodynamics at different time intervals during ischemia and reperfusion was observed after abatacept administration. The maintained enzyme levels of anti-oxidants v/s oxidants along with cardiac injury markers correlate with the histopathology findings. The inhibition of CD28 T-cell activation abates the release of inflammatory markers and related signaling pathways proteins showing the efficacy of Abatacept. On Investigation, expression of Nrf-2, Hsp27, and Hsp 70 thereby showing efficacy of Abatacept in cardiovascular models. Conclusions: Abatacept was found potent drug because of its co-stimulation inhibitor activity, and hence, it inhibits inflammation, oxidation, and apoptosis in models of myocardial infarction and could be beneficial for humans after designated clinical trials.