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NBCe1 Na+-HCO3- cotransporter ablation causes reduced apoptosis following cardiac ischemia-reperfusion injury in vivo.

ABSTRACT: AIM:To investigate the hypothesis that cardiomyocyte-specific loss of the electrogenic NBCe1 Na+-HCO3 - cotransporter is cardioprotective during in vivo ischemia-reperfusion (IR) injury. METHODS:An NBCe1 (Slc4a4 gene) conditional knockout mouse (KO) model was prepared by gene targeting. Cardiovascular performance of wildtype (WT) and cardiac-specific NBCe1 KO mice was analyzed by intraventricular pressure measurements, and changes in cardiac gene expression were determined by RNA Seq analysis. Response to in vivo IR injury was analyzed after 30 min occlusion of the left anterior descending artery followed by 3 h of reperfusion. RESULTS:Loss of NBCe1 in cardiac myocytes did not impair cardiac contractility or relaxation under basal conditions or in response to ?-adrenergic stimulation, and caused only limited changes in gene expression patterns, such as those for electrical excitability. However, following ischemia and reperfusion, KO heart sections exhibited significantly fewer apoptotic nuclei than WT sections. CONCLUSION:These studies indicate that cardiac-specific loss of NBCe1 does not impair cardiovascular performance, causes only minimal changes in gene expression patterns, and protects against IR injury in vivo .

SUBMITTER: Vairamani K

PROVIDER: S-EPMC6189072 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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NBCe1 Na<sup>+</sup>-HCO3<sup>-</sup> cotransporter ablation causes reduced apoptosis following cardiac ischemia-reperfusion injury <i>in vivo</i>.

Vairamani Kanimozhi K Prasad Vikram V Wang Yigang Y Huang Wei W Chen Yinhua Y Medvedovic Mario M Lorenz John N JN Shull Gary E GE

World journal of cardiology 20180901 9

<h4>Aim</h4>To investigate the hypothesis that cardiomyocyte-specific loss of the electrogenic NBCe1 Na<sup>+</sup>-HCO<sub>3</sub> <sup>-</sup> cotransporter is cardioprotective during <i>in vivo</i> ischemia-reperfusion (IR) injury.<h4>Methods</h4>An NBCe1 (<i>Slc4a4</i> gene) conditional knockout mouse (KO) model was prepared by gene targeting. Cardiovascular performance of wildtype (WT) and cardiac-specific NBCe1 KO mice was analyzed by intraventricular pressure measurements, and changes in ...[more]

PMID: 30344957

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Project description:K+/Cl- cotransporter 2 (KCC2) is a major Cl- extruder in mature neurons and is responsible for the establishment of low intracellular [Cl-], necessary for fast hyperpolarizing GABAA-receptor mediated synaptic inhibition. Electrogenic sodium bicarbonate cotransporter 1 (NBCe1) is a pH regulatory protein expressed in neurons and glial cells. An interactome study identified NBCe1 as a possible interaction partner of KCC2. In this study, we investigated the putative effect of KCC2/NBCe1 interaction in baseline and the stimulus-induced phosphorylation pattern and function of KCC2. Primary mouse hippocampal neuronal cultures from wildtype (WT) and Nbce1-deficient mice, as well as HEK-293 cells stably transfected with KCC2WT, were used. The results show that KCC2 and NBCe1 are interaction partners in the mouse brain. In HEKKCC2 cells, pharmacological inhibition of NBCs with S0859 prevented staurosporine- and 4-aminopyridine (4AP)-induced KCC2 activation. In mature cultures of hippocampal neurons, however, S0859 completely inhibited postsynaptic GABAAR and, thus, could not be used as a tool to investigate the role of NBCs in GABA-dependent neuronal networks. In Nbce1-deficient immature hippocampal neurons, baseline phosphorylation of KCC2 at S940 was downregulated, compared to WT, and exposure to staurosporine failed to reduce pKCC2 S940 and T1007. In Nbce1-deficient mature neurons, baseline levels of pKCC2 S940 and T1007 were upregulated compared to WT, whereas after 4AP treatment, pKCC2 S940 was downregulated, and pKCC2 T1007 was further upregulated. Functional experiments showed that the levels of GABAAR reversal potential, baseline intracellular [Cl-], Cl- extrusion, and baseline intracellular pH were similar between WT and Nbce1-deficient neurons. Altogether, our data provide a primary description of the properties of KCC2/NBCe1 protein-protein interaction and implicate modulation of stimulus-mediated phosphorylation of KCC2 by NBCe1/KCC2 interaction-a mechanism with putative pathophysiological relevance.

Dataset Information

NBCe1 Na+-HCO3- cotransporter ablation causes reduced apoptosis following cardiac ischemia-reperfusion injury in vivo.

Publications

NBCe1 Na<sup>+</sup>-HCO3<sup>-</sup> cotransporter ablation causes reduced apoptosis following cardiac ischemia-reperfusion injury <i>in vivo</i>.

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