N-n-butyl haloperidol iodide ameliorates hypoxia/reoxygenation injury through modulating the LKB1/AMPK/ROS pathway in cardiac microvascular endothelial cells
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Binger Lu1, Bin Wang3, Shuping Zhong2, Yanmei Zhang3, Fenfei Gao3, Yicun Chen3, Fuchun Zheng1, Ganggang Shi3,4
1Department of Pharmacy, The First Affiliated Hospital, Shantou University Medical College, Shantou 515041, Guangdong, China
2Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California 90033, USA
3Department of Pharmacology, Shantou University Medical College, Shantou 515041, Guangdong, China
4Department of Cardiovascular Diseases, The First Affiliated Hospital, Shantou University Medical College, Shantou 515041, Guangdong, China
Fuchun Zheng, email: [email protected]
Ganggang Shi, email: [email protected]
Keywords: N-n-butyl haloperidol iodide, LKB1/AMPK/ROS, hypoxia/reoxygenation, cardiac microvascular endothelial cells
Received: March 19, 2016 Accepted: April 16, 2016 Published: May 05, 2016
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.
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