Inhibitory G-protein-mediated modulation of slow delayed rectifier potassium channels contributes to increased susceptibility to arrhythmogenesis in aging heart

被引：7

作者：

Zou, Sihao ^{[1
]}

Qiu, Suhua ^{[1
]}

Su, Shi ^{[1
]}

Zhang, Jiali ^{[1
]}

Sun, Jinglei ^{[1
]}

Wang, Yuhong ^{[2
]}

Shi, Chenxia ^{[1
]}

Xu, Yanfang ^{[1
]}

机构：

[1] Hebei Med Univ, Dept Pharmacol, Key Lab New Drug Pharmacol & Toxicol, Shijiazhuang, Hebei, Peoples R China

[2] Chinese Acad Med Sci & Peking Union Med Coll, Inst Masteria Med, Beijing, Peoples R China

来源：

HEART RHYTHM | 2021年 / 18卷 / 12期

基金：

中国国家自然科学基金;

关键词：

Aging; Arrhythmias; beta-Adrenoceptor; Delayed rectifier K+ current; Inhibitory G protein; G-BETA-GAMMA; I-KS; REPOLARIZATION; ARRHYTHMIAS; MECHANISMS; ROLES; FORM;

D O I：

10.1016/j.hrthm.2021.09.014

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BACKGROUND Slow delayed rectifier potassium current (I-Ks) is an important component of repolarization reserve during sympathetic nerve excitement. However, little is known about age-related functional changes of I-Ks and its involvement in age-dependent arrhythmogenesis. OBJECTIVE The purpose of this study was to investigate age-related alteration of the I-Ks response to beta-adrenergic receptor (beta AR) activation. METHODS Dunkin-Hartley guinea pigs were used. Whole-cell patch-clamp recording was used to record K+ currents. Optical mapping of membrane potential was performed in ex vivo heart. RESULTS There was no difference in I-Ks density in ventricular cardiomyocytes between young and old guinea pigs. However, in contrast to I-Ks potentiation in young hearts, isoproterenol (ISO) evoked an acute inhibition on IKs in a concentration-dependent manner in old guinea pig hearts. The beta(2)AR antagonist, but not beta(1)AR antagonist, reversed the inhibitory response. Preincubation of cardiomyocytes with the inhibitory G protein (Gi) inhibitor pertussis toxin (PTX) also reversed the inhibitory response. In HEK293 cells cotransfected with cloned I-Ks channel and beta(2)AR, ISO enhanced the current but reduced it when cells were cotransfected with Gi2, and PTX restored the ISO-induced excitatory response. Moreover, in aging cardiomyocytes, G beta gamma inhibitor gallein, PLC inhibitor U73122, or protein kinase C inhibitor Bis-1 prevented the reduction of I-Ks by ISO. Furthermore, cardiac-specific Gi2 overexpression in young guinea pigs predisposed the heart to ventricular tachyarrhythmias. PTX pretreatment protected the hearts from ventricular arrhythmias. CONCLUSION beta AR activation acutely induces an inhibitory I-Ks response in aging guinea pig hearts through beta(2)AR-Gi signaling, which contributes to increased susceptibility to arrhythmogenesis in aging hearts.

引用

页码：2197 / 2209

页数：13

共 27 条

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