Homocysteine-induced electrical remodeling via the mediation of IP3R1/Nav1.5 signaling pathway

Inositol-1,4,5-triphosphate-receptor 1 (IP₃R1), a CA²⁺ channel in the sarcoplasmic reticulum membrane, is an effective regulator of CA²⁺ release involved in the pathology of most cardiovascular diseases. Our study aim to investigate the underlying mechanism by which IP₃R1 signaling mediates the process of homocysteine (Hcy)-induced CA²⁺ accumulation via interaction with sodium current (Nav1.5) in atrium. We utilized whole-cell patch-clamp analysis and flow cytometry to detect the abnormal electrical activity in mouse atrial myocytes (MACs) obtained from C57B6 mice fed with high-Hcy diet. The results represented not only an increase in protein levels of Nav1.5 and IP₃R1, but also an enhanced intracellular levels of CA²⁺, and prolonged action potential duration (APD). However, the inhibition of IP₃R1 or Nav1.5 gene could both attenuate CA²⁺ accumulation in MACs triggered by Hcy, as well as abnormal electrical activity. In addition, Hcy increased the interaction between IP₃R1 and Nav1.5. These data suggest that Hcy induced CA²⁺ accumulation is mediated by the IP₃R1/Nav1.5 signaling pathway, accompanied with the influx of Na⁺ and CA²⁺, which act as triggers for electrical remodeling.