title: Aberrant dynamin 2-dependent Na(+) /H(+) exchanger-1 trafficking contributes to cardiomyocyte apoptosis.
abstract: Sarcolemmal Na(+) /H(+) exchanger 1 (NHE1) activity is essential for the intracellular pH (pHi ) homeostasis in cardiac myocytes. Emerging evidence indicates that sarcolemmal NHE1 dysfunction was closely related to cardiomyocyte death, but it remains unclear whether defective trafficking of NHE1 plays a role in the vital cellular signalling processes. Dynamin (DNM), a large guanosine triphosphatase (GTPase), is best known for its roles in membrane trafficking events. Herein, using co-immunoprecipitation, cell surface biotinylation and confocal microscopy techniques, we investigated the potential regulation on cardiac NHE1 activity by DNM. We identified that DNM2, a cardiac isoform of DNM, directly binds to NHE1. Overexpression of a wild-type DNM2 or a dominant-negative DNM2 mutant with defective GTPase activity in adult rat ventricular myocytes (ARVMs) facilitated or retarded the internalization of sarcolemmal NHE1, whereby reducing or increasing its activity respectively. Importantly, the increased NHE1 activity associated with DNM2 deficiency led to ARVMs apoptosis, as demonstrated by cell viability, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling assay, Bcl-1/Bax expression and caspase-3 activity, which were effectively rescued by pharmacological inhibition of NHE1 with zoniporide. Thus, our results demonstrate that disruption of the DNM2-dependent retrograde trafficking of NHE1 contributes to cardiomyocyte apoptosis.
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China; Institute of Medical Genetics, Tongji University, Shanghai, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.forename: Jiangchuan
authors.initials: J
authors.lastname: Ye
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.forename: Dasheng
authors.initials: D
authors.lastname: Zhang
authors.forename: Dandan
authors.initials: D
authors.lastname: Liang
authors.forename: Xinran
authors.initials: X
authors.lastname: Xu
authors.forename: Man
authors.initials: M
authors.lastname: Qi
authors.forename: Changming
authors.initials: C
authors.lastname: Li
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Yuzhen
authors.initials: Y
authors.lastname: Zhang
authors.forename: Zhaonian
authors.initials: Z
authors.lastname: Zhou
authors.forename: Xingqun
authors.initials: X
authors.lastname: Liang
authors.forename: Jue
authors.initials: J
authors.lastname: Li
authors.forename: Luying
authors.initials: L
authors.lastname: Peng
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhu
authors.forename: Yi-Han
authors.initials: YH
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D034285:Dynamin II / Q000172:deficiency / Q000378:metabolism*; D057809:HEK293 Cells; D006352:Heart Ventricles / Q000166:cytology; D006801:Humans; D008297:Male; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D012508:Sarcolemma / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*
chemical_list: D017923:Sodium-Hydrogen Exchangers; D034285:Dynamin II
keywords: Na+/H+ exchanger 1; apoptosis; cardiomyocytes; dynamin; trafficking