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
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
收藏
页码:2197 / 2209
页数:13
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