title: Opening of the inward rectifier potassium channel alleviates maladaptive tissue repair following myocardial infarction.
abstract: Activation of the inward rectifier potassium current (IK1) channel has been reported to be associated with suppression of ventricular arrhythmias. In this study, we tested the hypothesis that opening of the IK1 channel with zacopride (ZAC) was involved in the modulation of tissue repair after myocardial infarction. Sprague-Dawley rats were subject to coronary artery ligation and ZAC was administered intraperitoneally (15 µg/kg/day) for 28 days. Compared with the ischemia group, treatment with ZAC significantly reduced the ratio of heart/body weight and the cross-sectional area of cardiomyocytes, suggesting less cardiac hypertrophy. ZAC reduced the accumulation of collagen types I and III, accompanied with decrease of collagen area, which were associated with a reduction of collagen deposition in the fibrotic myocardium. Echocardiography showed improved cardiac function, evidenced by the reduced left ventricular end-diastolic dimension and left ventricular end-systolic dimension, and the increased ejection fraction and fractional shortening in ZAC-treated animals (all P < 0.05 vs. ischemia group). In coincidence with these changes, ZAC up-regulated the protein level of the IK1 channel and down-regulated the phosphorylation of mammalian target of rapamycin (mTOR) and 70-kDa ribosomal protein S6 (p70S6) kinase. Administration of chloroquine alone, an IK1 channel antagonist, had no effect on all the parameters measured, but significantly blocked the beneficial effects of ZAC on cardiac repair. In conclusion, opening of the IK1 channel with ZAC inhibits maladaptive tissue repair and improves cardiac function, potentially mediated by the inhibition of ischemia-activated mTOR-p70S6 signaling pathway via the IK1 channel. So the development of pharmacological agents specifically targeting the activation of the IK1 channel may protect the heart against myocardial ischemia-induced cardiac dysfunction.
authors.affiliation: Department of Human Anatomy, Shanxi Medical University, Taiyuan 030001, China ljjlcf@126.com.
authors.forename: Chengfang
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Physiology, Shanxi Medical University, Taiyuan 030001, China.
authors.forename: Enli
authors.initials: E
authors.lastname: Liu
authors.affiliation: Department of Health Statistics, Shanxi Medical University, Taiyuan 030001, China.
authors.forename: Tiane
authors.initials: T
authors.lastname: Luo
authors.affiliation: Department of Physiology, Shanxi Medical University, Taiyuan 030001, China.
authors.forename: Weifang
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Human Anatomy, Shanxi Medical University, Taiyuan 030001, China.
authors.forename: Rongli
authors.initials: R
authors.lastname: He
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001835:Body Weight; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D003094:Collagen / Q000378:metabolism; D006439:Hemodynamics; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism / Q000503:physiopathology*; D009929:Organ Size; D010766:Phosphorylation; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014945:Wound Healing
chemical_list: D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D024661:Potassium Channels, Inwardly Rectifying; D003094:Collagen; C055971:zacopride; C546845:mTOR protein, rat; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases
keywords: cardiac repair; inward rectifier potassium channel; mTOR-p70S6; myocardial infarction; zacopride