부산대학교 도서관

Introduction: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 (IKACh).Hypothesis:We tested the hypothesis that CS stimulates phosphatidylinositol 4-phosphate 5-kinase alpha (PIP5K) signaling, leading to increased cellular phosphatidylinositol 4,5- bisphosphate (PiP2) levels, and subsequent IKAChactivation and AF perpetuation.Methods:We used patch clamp in HEK293 cells expressing Kir3.1 and Kir3.4, the molecular correlates of IKACh, cultured in the presence of 5% CS extracts. In vivo inducibility of AF was assessed in mice exposed to CS for 8 weeks.Results:In HEK293 cells, 24 h incubation with CSE increased the cellular PiP2 levels, and increased IKACh. Addition of 5 uM ISA, an inhibitor of PIP5K, abrogated the CS effects on IKACh,indicating that CS activates PIP5K. Finally, intrajugular injection of tertiapinQ, an IKAChblocker, terminated atrial fibrillation in mice exposed to CS for 8 weeks.Conclusions:Cigarette smoke modifies the atrial electrophysiological substrate, leading to arrhythmogenesis, in part, through IKAChactivation by increasing the cellular levels of PiP2.