title: N-n-butyl haloperidol iodide ameliorates hypoxia/reoxygenation injury through modulating the LKB1/AMPK/ROS pathway in cardiac microvascular endothelial cells.
abstract: 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.
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital, Shantou University Medical College, Shantou 515041, Guangdong, China.
authors.forename: Binger
authors.initials: B
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou 515041, Guangdong, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Shuping
authors.initials: S
authors.lastname: Zhong
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou 515041, Guangdong, China.
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou 515041, Guangdong, China.
authors.forename: Fenfei
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou 515041, Guangdong, China.
authors.forename: Yicun
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital, Shantou University Medical College, Shantou 515041, Guangdong, China.
authors.forename: Fuchun
authors.initials: F
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou 515041, Guangdong, China.|Department of Cardiovascular Diseases, The First Affiliated Hospital, Shantou University Medical College, Shantou 515041, Guangdong, China.
authors.forename: Ganggang
authors.initials: G
authors.lastname: Shi
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D042783:Endothelial Cells / Q000378:metabolism*; D006220:Haloperidol / Q000031:analogs & derivatives* / Q000494:pharmacology; D007511:Ischemia / Q000188:drug therapy; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C482574:N-n-butyl haloperidol iodide; D017382:Reactive Oxygen Species; D007770:L-Lactate Dehydrogenase; D017346:Protein Serine-Threonine Kinases; C488755:Stk11 protein, rat; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D006220:Haloperidol; D000111:Acetylcysteine
keywords: LKB1/AMPK/ROS; N-n-butyl haloperidol iodide; cardiac microvascular endothelial cells; hypoxia/reoxygenation