N-n-butyl haloperidol iodide ameliorates hypoxia/reoxygenation injury through modulating the LKB1/AMPK/ROS pathway in cardiac microvascular endothelial cells

Endothelial cells are highly sensitive to hypoxia and contribute to myocardial ischemia/reperfusion injury. We have reported that N-n-butyl haloperidol iodide (F2) can attenuate hypoxia/reoxygenation (H/R) injury in cardiac microvascular endothelial cells (CMECs). However, the molecular mechanisms r...

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Published in:Oncotarget 2016-06, Vol.7 (23), p.34800-34810
Main Authors: Lu, Binger, Wang, Bin, Zhong, Shuping, Zhang, Yanmei, Gao, Fenfei, Chen, Yicun, Zheng, Fuchun, Shi, Ganggang
Format: Article
Language:English
Subjects:
Acetylcysteine - pharmacology
AMP-Activated Protein Kinases - antagonists & inhibitors
AMP-Activated Protein Kinases - metabolism
Animals
Apoptosis - drug effects
Cell Hypoxia - drug effects
Cell Survival - drug effects
Endothelial Cells - metabolism
Haloperidol - analogs & derivatives
Haloperidol - pharmacology
Ischemia - drug therapy
L-Lactate Dehydrogenase - metabolism
Phosphorylation - drug effects
Protein-Serine-Threonine Kinases - metabolism
Rats
Rats, Sprague-Dawley
Reactive Oxygen Species - metabolism
Research Paper
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Summary:Endothelial cells are highly sensitive to hypoxia and contribute to myocardial ischemia/reperfusion injury. We have reported that N-n-butyl haloperidol iodide (F2) can attenuate hypoxia/reoxygenation (H/R) injury in cardiac microvascular endothelial cells (CMECs). However, the molecular mechanisms remain unclear. Neonatal rat CMECs were isolated and subjected to H/R. Pretreatment of F2 leads to a reduction in H/R injury, as evidenced by increased cell viability, decreased lactate dehydrogenase (LDH) leakage and apoptosis, together with enhanced AMP-activated protein kinase (AMPK) and liver kinase B1 (LKB1) phosphorylation in H/R ECs. Blockade of AMPK with compound C reversed F2-induced inhibition of H/R injury, as evidenced by decreased cell viability, increased LDH release and apoptosis. Moreover, compound C also blocked the ability of F2 to reduce H/R-induced reactive oxygen species (ROS) generation. Supplementation with the ROS scavenger N-acetyl-L-cysteine (NAC) reduced ROS levels, increased cell survival rate, and decreased both LDH release and apoptosis after H/R. In conclusion, our data indicate that F2 may mitigate H/R injury by stimulating LKB1/AMPK signaling pathway and subsequent suppression of ROS production in CMECs.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.9186