Department of Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.
Mol Biol Rep. 2024 Apr 16;51(1):520. doi: 10.1007/s11033-024-09421-9.
Mutations in human ether-à-go-go-related gene (hERG) potassium channels are closely associated with long QT syndrome (LQTS). Previous studies have demonstrated that macrolide antibiotics increase the risk of cardiovascular diseases. To date, the mechanisms underlying acquired LQTS remain elusive.
A novel hERG mutation I1025N was identified in an azithromycin-treated patient with acquired long QT syndrome via Sanger sequencing. The mutant I1025N plasmid was transfected into HEK-293 cells, which were subsequently incubated with azithromycin. The effect of azithromycin and mutant I1025N on the hERG channel was evaluated via western blot, immunofluorescence, and electrophysiology techniques.
The protein expression of the mature hERG protein was down-regulated, whereas that of the immature hERG protein was up-regulated in mutant I1025N HEK-293 cells. Azithromycin administration resulted in a negative effect on the maturation of the hERG protein. Additionally, the I1025N mutation exerted an inhibitory effect on hERG channel current. Moreover, azithromycin inhibited hERG channel current in a concentration-dependent manner. The I1025N mutation and azithromycin synergistically decreased hERG channel expression and hERG current. However, the I1025N mutation and azithromycin did not alter channel gating dynamics.
These findings suggest that hERG gene mutations might be involved in the genetic susceptibility mechanism underlying acquired LQTS induced by azithromycin.
人类 ether-à-go-go 相关基因（hERG）钾通道的突变与长 QT 综合征（LQTS）密切相关。先前的研究表明，大环内酯类抗生素会增加心血管疾病的风险。迄今为止，获得性 LQTS 的发病机制仍不清楚。
通过 Sanger 测序在接受阿奇霉素治疗的获得性长 QT 综合征患者中发现了一种新型 hERG 突变 I1025N。将突变型 I1025N 质粒转染至 HEK-293 细胞，然后用阿奇霉素孵育。通过 Western blot、免疫荧光和电生理学技术评估阿奇霉素和突变型 I1025N 对 hERG 通道的影响。
成熟 hERG 蛋白的蛋白表达下调，而突变型 I1025N HEK-293 细胞中的未成熟 hERG 蛋白表达上调。阿奇霉素给药对 hERG 蛋白的成熟产生负面影响。此外，I1025N 突变对 hERG 通道电流具有抑制作用。此外，阿奇霉素以浓度依赖性方式抑制 hERG 通道电流。I1025N 突变和阿奇霉素协同降低 hERG 通道表达和 hERG 电流。然而，I1025N 突变和阿奇霉素并未改变通道门控动力学。
这些发现表明，hERG 基因突变可能参与了阿奇霉素诱导的获得性 LQTS 的遗传易感性机制。
