Abstract

# 435 The role of macrophage migration inhibitory factor in the regulation of connexin 43 in atrial myocytes {#article-title-2} Introduction: Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. Recent findings have demonstrated a mechanistic link between inflammatory and the development of AF. Macrophage migration inhibitory factor (MIF), a pleiotropic cytokine, controls the inflammatory ‘set point’ by regulating the release of other pro-inflammatory cytokines. Recent studies have revealed that Connexin 43 (Cx 43) not only is involved in the electrical conductivity between the cells, but also forms a complex with PKP2 and Na+ channel to affect the sodium current. The purpose of this study is to observe the role of MIF in the expression of Cx43, and the role of Cx43 in the regulation of calcium channel current in atrial myocytes. Methods: Cx 43 expression in human atrial tissues and HL-1 cells were determined by Western blot and Real time PCR. Whole-cell voltage-clamp recordings and Real time PCR were used to study the regulation and expression of ICa,L and ICa,T in HL-1 cells before and after Cx 43 siRNA knocking down. Results: Expression levels of Cx 43 mRNA and protein are significantly reduced while MIF expression levels were increased in patients with AF. In HL-1 cells, the depression of Cx 43 expression levels induced by rMIF was prevented by ERK 1/2 inhibitor U0126, but not Src inhibitor Genistein and PP1. Both ICa,L and ICa,T are reduced after Cx 43 siRNA knocking down, probably by down-regulation of L type calcium channel a1C subunit and T type calcium channel a1G subunit. Conclusion: These results implicate MIF in the pathological mechanism of AF, probably by decreasing Cx43 expression through the activation of ERK1/2 kinases in atrial myocytes. And ICa,L and ICa,T are regulated directly by Cx43, implicate involvement of Cx 43 in the electrical remodeling. # 436 Up-regulation of myocardial connexin-43 by melatonin: novel mechanism involved in its antiarrhythmic effects in spontaneously hypertensive rats. {#article-title-3} Background and Purpose: It has been reported that melatonin can regulate blood pressure in humans as well as animals but its antiarrhythmic effects are less known. Circulating levels of melatonin are decreased in patients with CVD as well as in spontaneously hypertensive rats (SHR). We examined whether treatment with melatonin will affect both propensity of SHR heart to malignant arrhythmias and electrical coupling protein, connexin-43 (Cx43). Design and Methods: SHR and healthy rats fed a standard rat chow received melatonin (40 mikrog/ml/day) for 4 weeks and were compared with untreated rats. Myocardial Cx43 gene and protein expression as well as its functional ( phosphorylated) forms were examined. PKC-epsilon (involved in Cx43 phosphorylation) and PKC-delta (involved in myocardial remodeling) as well as myocardial distribution of Cx43 were determined. Isolated Langendorff-perfused heart was used to test its susceptibility to electrically inducible ventricular fibrillation (VF). Key Results: Melatonin significantly reduced blood pressure but did not affect body, heart and left ventricular weights of SHR. Compared to healthy rats the threshold to induce sustained VF was lower in SHR (18.7+2 vs 29.0+5 mA, p<0.05) and significantly increased in melatonin-treated SHR to 33.0+4 mA. Myocardial Cx43 mRNA levels did not differ from healthy rats but total Cx43 protein and its phosphorylated forms were decreased in SHR heart left ventricle. In contrast, melatonin treatment resulted in up-regulation of Cx43 and attenuation of its abnormal distribution in SHR. Moreover, melatonin normalized myocardial PKC-delta expression and enhanced PKC-epsilon in SHR hearts. Conclusions: Results indicate antiarrhythmic effects of melatonin in hypertensive rats that can be, in part, attributed to up-regulation of myocardial Cx43 and PKC signaling. Findings support monitoring of melatonin levels and its supplementation in patients with CVD. This work was supported by VEGA 2/0046/12, SK-CZ-0027-11 and SKS grants.

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