Necrostatin-1 reduces cardiac and mitochondrial dysfunction in prediabetic rats.

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High-fat diet (HFD) consumption induces prediabetes and left ventricular dysfunction through many pathways including cell death pathway like necroptosis. Although the benefit of necroptosis inhibitor (necrostatin-1 or Nec-1) in the brain of prediabetic rats was shown, the effects of Nec-1 on cardiac autonomic function, blood pressure, cardiac function, along with its mechanistic insight 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 three 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 normal diet-fed rats and vehicle 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 had cardiac autonomic imbalance, high blood pressure, and cardiac dysfunction, together with 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 reducing 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 of peripheral metabolic function, leading to an improved cardiac function in prediabetic rats.