Can J Physiol Pharmacol. 2013 Aug;91(8):633-9.

Melatonin attenuates hypertension-related proarrhythmic myocardial maladaptation of connexin-43 and propensity of the heart to lethal arrhythmias.

Tamara Benova, Csilla Viczenczova, Jana Radosinska, Barbara Bacova, Vladimir Knezl, Victor Dosenko, Peter Weismann, Michal Zeman, Jana Navarova, and Narcis Tribulova

Institute for Heart Research, Slovak Academy of Sciences, 840 05 Bratislava, Dúbravská cesta 9, PO Box 104, Bratislava, Slovakia.

 

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.

PMID: 23889002

 

Supplement:

Melatonin is an important chronobiological regulator that is released from pineal gland with peak during the night. This hormone is also involved in cardiovascular physiology and blood pressure regulation. Besides, melatonin exhibits antioxidant effects by acting as a free radical scavenger. These effects have been shown implicated in acute cardioprotection against ischemia/reperfusion injury and arrhythmias. The question arose whether melatonin might protect hypertensive rats that are prone to malignant arrhythmias and whether electrical coupling protein, connexin-43 (Cx43) might be involved in its antiarrhythmic effects. We have demonstrated that administration of melatonin for five weeks to SHR resulted in decrease of blood pressure and increase of threshold to induce sustained VF.

Fig.1a

Fig.1b

Figure 1. Representative continuous recordings from isolated perfused heart showing the incidence of sustained VF, which was induced by burst of electrical stimulation at 20 mA in nontreated SHR while only very short transient VF was induced in melatonin-treated SHR.

Antiarrhythmic effect of melatonin was linked with up-regulation of myocardial Cx43, which forms intercellular channels that are essential for electrical cell-to-cell coupling and myocardial synchronization. Melatonin also modulated myocardial PKC signaling. Possible mechanisms of melatonin actions are illustrated in Fig. 2.

Fig.2Figure 2. Proposed mechanisms of melatonin action on myocardial Cx43 expression and distribution in SHR heart. Cardiac tissue contains both of the high affinity, Gi protein-coupled membrane melatonin receptors1 (MT1R, MT2R). The signal transduction mechanisms involve a number of intracellular signaling processes, e.g. activation of phospholipase C (PLC) followed by production of diacylglycerol (DAG), which activates protein kinase C (PKC)2,3. PKC by phosphorylation of Cx43 can modulate channels function as well as its myocardial distribution and subsequently gap junctional intercellular communication (GJIC). Activation of PKC also affects transcription factors c-FOS and cJUN, which bind to conserved activator protein-1 in promoter region of Cx434 and hence increase Cx43 expression. In addition, melatonin exhibits receptor-independent actions due to its ability to scavenge free radicals (function as an antioxidant)3,5. Because free radicals enhance degradation of Cx43 melatonin can attenuate this process and preserve myocardial Cx43 levels. Altogether, protection of functional Cx43 by melatonin can affect GJIC and prevent myocardial electric instability resulting in increase of ventricular fibrillation threshold (VFT).

In the context of antiarrhythmic effects of melatonin it should be noted that several mechanisms of its action may coexist to cause multiple cellular response resulting in cardioprotection. Accordingly, it should be taken into account that melatonin inhibits Ca2+ influx and mobilization of Ca2+ from intracellular stores and exert anti-adrenergic action most likely via regulation of second messengers such as, cAMP, cGMP, InsP3 and [Ca2]i. Melatonin is also ligand for  the orphan nuclear hormone receptor superfamily RZR/ROR; the signal transduction mechanisms of these receptors remain ambiguous but their implication in regulation of myocardial Cx43 expression can not be ruled out. Noteworthy, melatonin synthesis is decreased in patients with cardiovascular diseases that are known to increase a risk for sudden cardiac death due to malignant arrhythmia. Thus, our findings may support the importance of the melatonin system as a potential therapeutic target.

 

References:

1. Sallinen P., Mänttäri S., Leskinen H., Ilves M., Vakkuri O., Ruskoaho H., Saarela S.: The effect of myocardial infarction on the synthesis, concentration and receptor expression of endogenous melatonin. J Pineal Res., 42(3): 254-260, 2007.

2. Vanecek J.: Cellular mechanisms of melatonin action. Physiol. rev., 78(3): 687-721, 1998.

3. Reiter RJ., Manchester LC., Fuentes-Broto L., Tan DX.: Cardiac hypertrophy and remodelling: pathophysiological consequences and protective effects of melatonin. J Hypertens., 28(1): S7-12, 2010.

4. Mitchell JA., Lye SJ.: Regulation of connexin43 expression by c-fos and c-jun in myometrial cells. Cell Commun Adhes. 8(4-6): 299-302, 2001.

5. Cardinali DP., Pévet P.: Basic aspects of melatonin action. Sleep Med Rev. 2(3):175-90, 1998.

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Figure 3. Research team of N. Tribulova. PhD., DSc., (on the left) includes C. Viczenczova, MSc., J. Radosinska MD, PhD., T. Benova, MSc., B. Bacova, PhD.

Contact:

N. Tribulova,  Institute for Heart Research, Slovak Academy of Sciences, Bratislava

E-mail: narcisa tribulova@savba.sk

Collaboration with M. Zeman, DrSc., Professor and Chair Dept. of Animal Physiology and Ethology,  Faculty of Life Sciences, Comenius University in Bratislava

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