title: Melatonin attenuates hypertension-related proarrhythmic myocardial maladaptation of connexin-43 and propensity of the heart to lethal arrhythmias.
abstract: We hypothesized that the pineal hormone melatonin, which exhibits cardioprotective effects, might affect myocardial expression of cell-to-cell electrical coupling protein connexin-43 (Cx43) and protein kinase C (PKC) signaling, and hence, the propensity of the heart to lethal ventricular fibrillation (VF). Spontaneously hypertensive (SHR) and normotensive Wistar rats fed a standard rat chow received melatonin (40 μg/mL in drinking water during the night) for 5 weeks, and were compared with untreated rats. Melatonin significantly reduced blood pressure and normalized triglycerides in SHR, whereas it decreased body mass and adiposity in Wistar rats. Compared with healthy rats, the threshold to induce sustained VF was significantly lower in SHR (18.3 ± 2.6 compared with 29.2 ± 5 mA; p < 0.05) and increased in melatonin-treated SHR and Wistar rats to 33.0 ± 4 and 32.5 ± 4 mA. Melatonin attenuated abnormal myocardial Cx43 distribution in SHR, and upregulated Cx43 mRNA, total Cx43 protein, and its functional phosphorylated forms in SHR, and to a lesser extent, in Wistar rat hearts. Moreover, melatonin suppressed myocardial proapoptotic PKCδ expression and increased cardioprotective PKCε expression in both SHR and Wistar rats. Our findings indicate that melatonin protects against lethal arrhythmias at least in part via upregulation of myocardial Cx43 and modulation of PKC-related cardioprotective signaling.
authors.affiliation: Institute for Heart Research, Slovak Academy of Sciences, 840 05 Bratislava, Dúbravská cesta 9, PO Box 104, Bratislava, Slovakia.
authors.forename: Tamara
authors.initials: T
authors.lastname: Benova
authors.forename: Csilla
authors.initials: C
authors.lastname: Viczenczova
authors.forename: Jana
authors.initials: J
authors.lastname: Radosinska
authors.forename: Barbara
authors.initials: B
authors.lastname: Bacova
authors.forename: Vladimir
authors.initials: V
authors.lastname: Knezl
authors.forename: Victor
authors.initials: V
authors.lastname: Dosenko
authors.forename: Peter
authors.initials: P
authors.lastname: Weismann
authors.forename: Michal
authors.initials: M
authors.lastname: Zeman
authors.forename: Jana
authors.initials: J
authors.lastname: Navarova
authors.forename: Narcis
authors.initials: N
authors.lastname: Tribulova
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D018031:Connexin 43 / Q000096:biosynthesis / Q000378:metabolism*; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008550:Melatonin / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D009206:Myocardium / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D002316:Cardiotonic Agents; D018031:Connexin 43; C580592:Gja1 protein, rat; D011493:Protein Kinase C; D008550:Melatonin