N-n-butyl haloperidol iodide mitigates myocardial ischemia/reperfusion injury through activation of SIRT1-Nrf2 signaling loop.

Abstract

N-n-butyl haloperidol iodide (F2), 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 F2 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 F2 depends on Nrf2 using a mouse heart I/R model. F2 (0.1, 0.2 or 0.4 mg/kg) or vehicle was intravenously injected to mice 5 min before reperfusion. Systemic administration of 0.4 mg/kg F2 led to a significant reduction in I/R injury, which was accompanied by enhanced activation of Nrf2 signaling. The cardioprotection conferred by F2 was largely abrogated in Nrf2-deficient mice. Importantly, we found F2-induced activation of Nrf2 is SIRT1-dependent, as pharmacologically inhibiting SIRT1 by the specific inhibitor EX527 blocked Nrf2 activation. Moreover, F2-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 F2 against myocardial I/R injury, and may provide new insights for the treatment of ischemic heart disease.