title: Reduction in dynamin-2 is implicated in ischaemic cardiac arrhythmias.
abstract: Ischaemic cardiac arrhythmias cause a large proportion of sudden cardiac deaths worldwide. The ischaemic arrhythmogenesis is primarily because of the dysfunction and adverse remodelling of sarcolemma ion channels. However, the potential regulators of sarcolemma ion channel turnover and function in ischaemic cardiac arrhythmias remains unknown. Our previous studies indicate that dynamin-2 (DNM2), a cardiac membrane-remodelling GTPase, modulates ion channels membrane trafficking in the cardiomyocytes. Here, we have found that DNM2 plays an important role in acute ischaemic arrhythmias. In rat ventricular tissues and primary cardiomyocytes subjected to acute ischaemic stress, the DNM2 protein and transcription levels were markedly down-regulated. This DNM2 reduction was coupled with severe ventricular arrhythmias. Moreover, we identified that the down-regulation of DNM2 within cardiomyocytes increases the action potential amplitude and prolongs the re-polarization duration by depressing the retrograde trafficking of Nav1.5 and Kir2.1 channels. These effects are likely to account for the DNM2 defect-induced arrhythmogenic potentials. These results suggest that DNM2, with its multi-ion channel targeting properties, could be a promising target for novel antiarrhythmic therapies.
authors.affiliation: Key Laboratory of Basic Research in Cardiology of the Ministry of Education of China, Tongji University, Shanghai, China; Institute of Medical Genetics, Tongji University, Shanghai, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Shi
authors.forename: Duanyang
authors.initials: D
authors.lastname: Xie
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.forename: Changming
authors.initials: C
authors.lastname: Li
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Fei
authors.initials: F
authors.lastname: Lv
authors.forename: Erlinda
authors.initials: E
authors.lastname: The
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Tianyou
authors.initials: T
authors.lastname: Yuan
authors.forename: Shiyi
authors.initials: S
authors.lastname: Wang
authors.forename: Jinjin
authors.initials: J
authors.lastname: Chen
authors.forename: Lei
authors.initials: L
authors.lastname: Pan
authors.forename: Zuoren
authors.initials: Z
authors.lastname: Yu
authors.forename: Dandan
authors.initials: D
authors.lastname: Liang
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhu
authors.forename: Yuzhen
authors.initials: Y
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Luying
authors.initials: L
authors.lastname: Peng
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Yi-Han
authors.initials: YH
authors.lastname: Chen
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019921:Biotinylation; D015153:Blotting, Western; D002478:Cells, Cultured; D034285:Dynamin II / Q000235:genetics / Q000378:metabolism*; D004562:Electrocardiography; D004594:Electrophysiology; D007124:Immunoenzyme Techniques; D007511:Ischemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C575188:KCNJ2 protein, rat; D062554:NAV1.5 Voltage-Gated Sodium Channel; D024661:Potassium Channels, Inwardly Rectifying; D012333:RNA, Messenger; C568322:Scn5a protein, rat; D034285:Dynamin II
keywords: Kir2.1; Nav1.5; dynamin-2; ion channels; ischaemic cardiac arrhythmias
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