P385Distinct contribution of cardiac connexins on regulating the action potential propagation in the healthy and diseased heart

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Cardiac gap junctions display distinct electrical properties in the different tissues that ensure the coordinated propagation of the action potential. They are clusters of intercellular gap junction channels (GJC) composed of connexins (Cxs) Cx40, Cx43, Cx45 and Cx30.2, which exhibit specific pattern of expression in the healthy heart. Importantly, in the diseased heart (e.g. atrial and ventricular fibrillations), a Cxs remodeling, i.e. altered expression and localization, and pro-arrhythmic electrical properties have been observed.

The aim of this study is to determine the role of Cx40, Cx43 and Cx45 in regulating the propagation of action potential. The mouse atrial phenotypic HL-1 cell line, owning a spontaneous contractile activity and that co-expresses Cx40, Cx43 and traces of Cx45, is used. Extracellular electrical recordings on microelectrodes arrays are performed to characterize the cardiac impulse propagation, i.e. the conduction velocity (CV) and direction. The electrical activity was recorded before and after pacing at frequencies of 2Hz, 5Hz, 10Hz and 30Hz that mimic the changing beating frequency in the healthy and diseased heart.

We observed that HL-1 cells display a spontaneous rhythmic coordinated activity of ≈1 Hz characterized by a CV ≈ 35 mm/s. After pacing, we observed that the higher the frequency, the slower the CV. Interestingly, the conduction becomes disorganized at 10 Hz, and chaotic and not homogeneous after burst stimulations (30Hz), similar to ECG recordings of atrial fibrillation observed in patients and animal models. This suggests that gap junction channels adapt to the frequency to ensure a safe propagation, up to a threshold that alters their electrical properties. SiRNA transfection that down-regulate each connexin will determine their specific contribution in regulating the CV. Biochemical characterization and patch clamp recordings on cell pairs are ongoing to correlate the GJC make-up and electrical properties to the distinct CV.

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