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N-n-butyl haloperidol iodide mediates cardioprotection via regulating AMPK/FoxO1 signalling.

ABSTRACT: Derangement of redox condition largely contributes to cardiac ischemia/reperfusion (I/R) injury. FoxO1 is a transcription factor which transcripts a series of antioxidants to antagonize I/R-induced oxidative myocardial damage. N-n-butyl haloperidol iodide (F₂ ) is a derivative derived from haloperidol structural modification with potent capacity of inhibiting oxidative stress. This investigation intends to validate whether cardio-protection of F₂ is dependent on FoxO1 using an in vivo mouse I/R model and if so, to further elucidate the molecular regulating mechanism. This study initially revealed that F₂ preconditioning led to a profound reduction in I/R injury, which was accompanied by attenuated oxidative stress and upregulation of antioxidants (SOD2 and catalase), nuclear FoxO1 and phosphorylation of AMPK. Furthermore, inactivation of FoxO1 with AS1842856 abolished the cardio-protective effect of F₂ . Importantly, we identified F₂ -mediated nuclear accumulation of FoxO1 is dependent on AMPK, as blockage of AMPK with compound C induced nuclear exit of FoxO1. Collectively, our data uncover that F₂ pretreatment exerts significant protection against post ischemic myocardial injury by its regulation of AMPK/FoxO1 pathway, which may provide a new avenue for treating ischemic disease.

SUBMITTER: Lu B

PROVIDER: S-EPMC10826434 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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N-n-butyl haloperidol iodide mediates cardioprotection via regulating AMPK/FoxO1 signalling.

Lu Binger B Wu Zhuomin Z He Weiliang W Feng Zikai Z Liao Jilin J Wang Bin B Zhang Yanmei Y Gao Fenfei F Shi Ganggang G Zheng Fuchun F

Journal of cellular and molecular medicine 20231121 2

Derangement of redox condition largely contributes to cardiac ischemia/reperfusion (I/R) injury. FoxO1 is a transcription factor which transcripts a series of antioxidants to antagonize I/R-induced oxidative myocardial damage. N-n-butyl haloperidol iodide (F<sub>2</sub> ) is a derivative derived from haloperidol structural modification with potent capacity of inhibiting oxidative stress. This investigation intends to validate whether cardio-protection of F<sub>2</sub> is dependent on FoxO1 using ...[more]

PMID: 37987145

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Project description:Early growth response-1 (Egr-1), a transcription factor which often underlies the molecular basis of myocardial ischemia/reperfusion (I/R) injury, and oxidative stress, is key to myocardial I/R injury. Silent information regulator of transcription 1(SIRT1) not only interacts with and is inhibited by Egr-1, but also downregulates reactive oxygen species (ROS) via the Forkhead box O1(FOXO1)/manganese superoxide dismutase (Mn-SOD) signaling pathway. N-n-butyl haloperidol iodide (F2), a new patented compound, protects the myocardium against myocardial I/R injury in various animal I/R models in vivo and various heart-derived cell hypoxia/reoxygenation (H/R) models in vitro. In addition, F2 can regulate the abnormal ROS/Egr-1 signaling pathway in cardiac microvascular endothelial cells (CMECs) and H9c2 cells after H/R. We studied whether there is an inverse Egr-1/ROS signaling pathway in H9c2 cells and whether the SIRT1/FOXO1/Mn-SOD signaling pathway mediates this. We verified a ROS/Egr-1 signaling loop in H9c2 cells during H/R and that F2 protects against myocardial H/R injury by affecting SIRT1-related signaling pathways. Knockdown of Egr-1, by siRNA interference, reduced ROS generation, and alleviated oxidative stress injury induced by H/R, as shown by upregulated mitochondrial membrane potential, increased glutathione peroxidase (GSH-px) and total SOD anti-oxidative enzyme activity, and downregulated MDA. Decreases in FOXO1 protein expression and Mn-SOD activity occurred after H/R, but could be blocked by Egr-1 siRNA. F2 treatment attenuated H/R-induced Egr-1 expression, ROS generation and other forms of oxidative stress injury such as MDA, and prevented H/R-induced decreases in FOXO1 and Mn-SOD activity. Nuclear co-localization between Egr-1 and SIRT1 was increased by H/R and decreased by either Egr-1 siRNA or F2. Therefore, our results suggest that Egr-1 inhibits the SIRT1/FOXO1/Mn-SOD antioxidant signaling pathway to increase ROS and perpetuate I/R injury. F2 inhibits induction of Egr-1 by H/R, thereby activating SIRT1/FOXO1/Mn-SOD antioxidant signaling and decreasing H/R-induced ROS, demonstrating an important mechanism by which F2 protects against myocardial H/R injury.

Dataset Information

N-n-butyl haloperidol iodide mediates cardioprotection via regulating AMPK/FoxO1 signalling.

Publications

N-n-butyl haloperidol iodide mediates cardioprotection via regulating AMPK/FoxO1 signalling.

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