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

Lu Han; Aping Wu; Qing Li; Zhen Xia; Yanqing Wu; Kui Hong; Zirong Xia; Juxiang Li

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

Am J Transl Res. 2020 Jul 15;12(7):3822-3841. eCollection 2020.

Authors

Lu Han¹, Aping Wu¹, Qing Li¹, Zhen Xia¹, Yanqing Wu¹, Kui Hong¹, Zirong Xia¹, Juxiang Li¹

Affiliation

¹ Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University Nanchang 330006, China.

PMID: 32774738
PMCID: PMC7407712

Abstract

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.

Keywords: Homocysteine; ICaL; INaL; IP3R1; Nav1.5; electrical remodeling.