Abstract 1139: Necrostatin-1 is a Novel Protector of Myocardial Infarction
To date, it has been difficult to investigate the potential mechanisms of necrosis, which is generally believed to be a passive cellular response to external damage. Recently, a new non-apoptotic pathway to necrosis called necroptosis was described by Yuan and colleagues. Given the central role of necrosis in myocardial infarction, we hypothesized that necrostatin-1, a specific inhibitor of necroptosis, can confer myocardial protection. Mouse hearts were subjected to 60 min of LAD ligation followed by 4 h of reperfusion. Necrostatin-1 (1.65 mg/kg, i.p.) was administered either 30 min before ligation or immediately after initiation of reperfusion. The infarct size/risk area was reduced from 51 ± 3% in the control to 20 ± 2.7% and 30 ± 3.6%, respectively (n=6, P<0.05). We also found that necrostatin-1 pretreatment reduced the troponin-I levels from 102 ± 6.8 ng/ml in the control plasma to 51 ± 5.7 ng/ml (P<0.05). Our studies show that necrostatin-1 confers myocardial protection when given 30 min before LAD ligation and immediately during reperfusion. This intriguing data suggests that necrostatin-1 might be an effective cardioprotective agent after myocardial infarction, which could have great clinical significance. Our studies also showed that necrostatin-1 confers additional protection in the presence of a pan-caspase inhibitor, zVAD.fmk (3.3 mg/kg, i.p.). The protective effect was not abolished in Akt kinase-deficient mutant mice. In conclusion, our experiments show that necrostatin-1 inhibits necroptosis during myocardial infarction and that its protective action is mediated by a caspase-independent pathway.