title: Involvement of K+ channel-dependant pathways in lipoxin A4-induced protective effects on hypoxia/reoxygenation injury of cardiomyocytes.
abstract: Studies have shown that lipoxin A4 (LXA4) and activation of LXA4 receptor provided protection against myocardial ischemia/reperfusion injury in animal models. However, the mechanisms by which LXA4 induced protective role on myocardial ischemia/reperfusion injury remains unclear. In the present studies, we investigated the protective effects of LXA4 on H9c2 cardiomyocytes exposed to hypoxia/reoxygenation (H/R) injury and involvement of heme oxygenase-1 (HO-1)- and K(+) channel-dependant pathways in the LXA4 action. H9c2 cardiomyocytes were pretreated with or without LXA4 or HO-1 specific interfering RNA (siRNA) or various blockers and openers of K(+) channels before exposing to H/R injury. The levels of lactate dehydrogenase (LDH) and creatine kinase (CK) in cellular supernatants and necrosis factor-α (TNF-α) in cellular lysates were measured by using ELISA. Expressions of HO-1 mRNA and protein were analyzed by using RT-PCR and Western blot respectively. Pretreatment of the cells undergoing H/R injury with LXA4 significantly reduced the LDH and CK levels induced by H/R injury, and increased the expressions and activity of HO-1. However, the protective effects of LXA4 were completely blocked by transfection of the cells with HO-1 siRNA, and were partially but significantly blocked by pretreatment of the cells with various blockers of K(+) channels. The LXA4-induced expressions of HO-1 in the cells were also inhibited by HO-1 siRNA and various blockers of K(+) channels. The inhibitory effects of LXA4 on enhanced TNF-α levels induced by H/R injury were abolished by transfection of the cells with HO-1 siRNA. In conclusion, the protective role of LXA4 on cardiomyocytes against H/R injury is related to upregulation of HO-1 via reduced production of TNF-α and activation of ATP-sensitive K(+) channels and calcium-sensitive K(+) channel.
authors.affiliation: Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, People's Republic of China.
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Chen
authors.forename: Sheng-Hua
authors.initials: SH
authors.lastname: Wu
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.forename: Yan-Rong
authors.initials: YR
authors.lastname: Tang
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D003402:Creatine Kinase / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D044045:Lipoxins / Q000378:metabolism* / Q000494:pharmacology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D015221:Potassium Channels / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015854:Up-Regulation
chemical_list: D044045:Lipoxins; D015221:Potassium Channels; D012333:RNA, Messenger; C040527:lipoxin A4; D051547:Heme Oxygenase-1; D003402:Creatine Kinase