The Arf6/PIP5K pathway activates IKACh in cigarette smoke mediated atrial fibrillation

Bojjibabu Chidipi; Mengmeng Chang; Obada Abou-Assali; Michelle Reiser; Zhi Tian; Diane Allen-Gipson; Sami F Noujaim

doi:10.1016/j.cellsig.2022.110475

The Arf6/PIP5K pathway activates IKACh in cigarette smoke mediated atrial fibrillation

Cell Signal. 2022 Dec:100:110475. doi: 10.1016/j.cellsig.2022.110475. Epub 2022 Sep 20.

Authors

Bojjibabu Chidipi¹, Mengmeng Chang², Obada Abou-Assali², Michelle Reiser², Zhi Tian³, Diane Allen-Gipson³, Sami F Noujaim²

Affiliations

¹ Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, United States of America.. Electronic address: chidipib@usf.edu.
² Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, United States of America.
³ Department of Pharmaceutical Science, USF Health Taneja College of Pharmacy, University of South Florida, Tampa, FL, United States of America.

PMID: 36150420
DOI: 10.1016/j.cellsig.2022.110475

Abstract

Cigarette smoking (CS) is a major cause of cardiovascular diseases. Smokers are at a significantly higher risk for developing atrial fibrillation (AF), a dangerous and abnormal heart rhythm. In the US, 15.5% of adults are current smokers, and it is becoming clear that CS is an independent risk factor for AF, but a detailed mechanistic understanding of how CS contributes to the molecular patho-electrophysiology of AF remains elusive. We investigated if CS related AF is in part mediated through a mechanism that depends on the cardiac acetylcholine activated inward rectifier potassium current (I_KACh). We tested the hypothesis that CS increases I_KACh via phosphatidylinositol 4-phosphate 5-kinase alpha (PIP5K) and ADP ribosylation factor 6 (Arf6) signaling, leading to AF perpetuation. In vivo inducibility of AF was assessed in mice exposed to CS for 8 weeks. AF duration was increased in CS exposed mice, and TertiapinQ, an I_KACh blocker prevented AF development in CS exposed mice. In HEK293 cells stably transfected with Kir3.1 and Kir3.4, the molecular correlates of I_KACh, CS exposure increased the expression of the Kir3.1 and Kir3.4 proteins at the cell surface, activated Arf6 and increased the I_KACh current. Inhibition of PIP5K, or of Kir3.1/Kir3.4 trafficking via Arf6 abrogated the CS effects on I_KACh. Cigarette smoke modifies the atrial electrophysiological substrate, leading to arrhythmogenesis, in part, through I_KACh activation via an Arf6/PIP5K dependent pathway.

Keywords: Arf6; Cigarette smoking; I(KACh); PIP5K; PiP2.