Mitochondrial dysfunction is linked with myocardial infarction (MI), a disorder in which Notch1 has attracted increasing attention. However, the involvement of Notch1 in mitochondrial impairment after an MI is poorly understood, as is the role of mitochondrial fusion-associated protein 2 (Mfn2). Moreover, whether melatonin potentiates the Notch1/Mfn2 pathway in post-MI cardiac damage remains unclear. In our study, small interfering RNAs against Notch1 or Mfn2 and Jagged1 peptide were delivered via intramyocardial injection. At 3 days after these treatments, MI was induced by ligation of the anterior descending branch. We found that this ablation of Notch1 or Mfn2 aggravated post-MI injury, including worsened mitochondrial damage and increased generation of reactive oxygen species (ROS). In contrast, Jagged1 improved mitochondrial structure and function, decreased ROS production and attenuated post-MI injury. Interestingly, though Mfn2 expression was mildly regulated by Notch1 signaling in myocardium, Mfn2 deficiency nearly eliminated the cardioprotection by Jagged1, as evidenced by suppressed cardiac function, aggravated myocardial fibrosis, increased cell apoptosis, worsened mitochondrial impairment and enhanced oxidative stress. These observations revealed that Mfn2 plays an indispensable role in protection against MI-induced injury by Notch1. The mechanism might involve disrupting a damaging cycle of mitochondrial damage and ROS generation. Furthermore, melatonin activated Notch1 signaling and increased Mfn2 expression were reversed by luzindole, a nonselective antagonist of the melatonin receptor. Notably, melatonin attenuated post-MI injury in normal mice, but not in mice deficient in Notch1 or Mfn2. These results demonstrate that melatonin attenuates post-MI injury via the Notch1/Mfn2 pathway in a receptor-dependent manner.
Keywords: Melatonin; Mfn2; Mitochondria; Myocardial infarction; Notch1; ROS.
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