2020 – Homocysteine-induced electrical remodeling via the mediation of IP 3 R1/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.