High fat diet (HFD) consumption induces prediabetes and left ventricular dysfunction through many pathways including the cell death pathway, necroptosis. Although benefits of necroptosis inhibitor (necrostatin-1 or Nec-1) in the brain of prediabetic rats have been shown, the effects of Nec-1 on cardiac autonomic function, blood pressure, and cardiac function, and the mechanisms involved have not been investigated. Male Wistar rats were fed with either a normal diet (n=8) or HFD (n=24) for 12 weeks to induce prediabetes. Prediabetic rats were randomly assigned into 3 interventional groups (n=8/group): 1) vehicle, 2) Nec-1 (1.65 mg/kg, sc injection), and 3) metformin (300 mg/kg, oral gavage feeding). Treatments lasted for 8 weeks. Normal saline was given to the vehicle group and a non-interventional group. Metabolic parameters, cardiac function and biochemical parameters were assessed. Prediabetic rats exhibited peripheral metabolic impairment as indicated by increased body weight, hyperinsulinemia with euglycemia, and dyslipidemia. Prediabetic rats also exhibited cardiac autonomic imbalance, high blood pressure, cardiac dysfunction, cardiac mitochondrial dysfunction, mitochondrial dynamic imbalance, and increased necroptosis and apoptosis. Treatment with Nec-1 did not affect peripheral metabolic parameters, however it effectively reduced cardiac autonomic imbalance, blood pressure, and cardiac dysfunction via reduced cardiac inflammation, necroptosis, mitochondrial dysfunction, and increased mitochondrial fusion. Treatment with metformin reduced peripheral metabolic impairment and cardiac dysfunction via decreased cardiac mitochondrial dysfunction, mitochondrial dynamic imbalance, and apoptosis. In summary, Nec-1 directly suppressed necroptosis, cardiac mitochondrial dysfunction, and increased mitochondrial fusion independent to peripheral metabolic function, leading to an improvement in cardiac function in prediabetic rats.
