N-N-Butyl Haloperidol Iodide Mitigates Myocardial Ischemia/Reperfusion Injury Through Activation of SIRT1-Nrf2 Signaling Loop

N-n-butyl haloperidol iodide (F-2), a derivative of haloperidol developed by our group, exhibits potent antioxidative properties and confers protection against cardiac ischemia/reperfusion (I/R) injury. The protective mechanisms by which F-2 ameliorates I/R injury remain obscure. The activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcription factor transactivating many antioxidative genes, also attenuates I/R-induced myocardial damage. The present study investigated whether the cardioprotective effect of F-2 depends on Nrf2 using a mouse heart I/R model. F-2 (0.1, 0.2 or 0.4 mg/kg) or vehicle was intravenously injected to mice 5 minutes before reperfusion. Systemic administration of 0.4 mg/kg F-2 led to a significant reduction in I/R injury, which was accompanied by enhanced activation of Nrf2 signaling. The cardioprotection conferred by F-2 was largely abrogated in Nrf2-deficient mice. Importantly, we found F-2-induced activation of Nrf2 is silent information regulator of transcription 1 (SIRT1)-dependent, as pharmacologically inhibiting SIRT1 by the specific inhibitor EX527 blocked Nrf2 activation. Moreover, F-2-upregulated expression of SIRT1 was also Nrf2-dependent, as Nrf2 deficiency inhibited SIRT1 upregulation. These results indicate that SIRT1-Nrf2 signaling loop activation is indispensable for the protective effect of F-2 against myocardial I/R injury and may provide new insights for the treatment of ischemic heart disease.