Aberrant dynamin 2-dependent Na(+) /H(+) exchanger-1 trafficking contributes to cardiomyocyte apoptosis.

Journal of cellular and molecular medicine 2013 Sep

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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. © 2013 The Authors. Journal of Cellular and Molecular Medicine Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Citation

Jun Li, Liang Xu, Jiangchuan Ye, Xiang Li, Dasheng Zhang, Dandan Liang, Xinran Xu, Man Qi, Changming Li, Hong Zhang, Jing Wang, Yi Liu, Yuzhen Zhang, Zhaonian Zhou, Xingqun Liang, Jue Li, Luying Peng, Weidong Zhu, Yi-Han Chen. Aberrant dynamin 2-dependent Na(+) /H(+) exchanger-1 trafficking contributes to cardiomyocyte apoptosis. Journal of cellular and molecular medicine. 2013 Sep;17(9):1119-27