Abstract
Patency of the ductus arteriosus (DA) is crucial for both fetal circulation and patients with DA-dependent congenital heart diseases (CHD). The Na+/Ca2+ exchanger 1 (NCX1) protein has been shown to play a key role in the regulation of vascular tone and is elevated in DA-dependent CHD. This current study was conducted to investigate the mechanisms underpinning the role of NCX1 in DA patency. Our data showed NCX1 expression was up-regulated in the DA of fetal mice. Up-regulation of NCX1 expression resulted in a concomitant decrease in cytosolic Ca2+ levels in human DA smooth muscle cells (DASMCs) and an inhibition of the proliferation and migration capacities of human DASMCs. Furthermore, treatment of DASMCs with KB-R7943, which can reduce Ca2+ influx, resulted in the inhibition of both cell proliferation and migration. These findings indicate that NCX1 may play a role in maintaining patent DA not only by preventing DA functional closure through reducing cytosolic Ca2+ level in DASMC but also by delaying the anatomical closure process. The latter delay is facilitated by the down-regulation of human DASMC proliferation and migration. It is also likely that a reduction in cytosolic Ca2+ levels inhibits the proliferation and migration capacities of human DASMCs in vitro.
Highlights
Three signaling pathways have been proposed to regulate ductus arteriosus (DA) patent: 1) Prostaglandin signaling; 2) ion channel pathways; and 3) cytochrome P450/endothelin-1 pathway[3]
In order to confirm the results of flow cytometry, we performed calcium imaging experiment, which showed the fluorescence intensity of the DA smooth muscle cells (DASMCs) transfected with Na+/Ca2+ exchanger 1 (NCX1)-cDNA was apparently reduced compared with negative control group (Fig. 2e)
We demonstrated for the first time that NCX1 messenger RNA (mRNA) and protein expression is apparently higher in fetal mouse DA compared with newborn mouse DA tissues
Summary
Three signaling pathways have been proposed to regulate DA patent: 1) Prostaglandin signaling; 2) ion channel pathways; and 3) cytochrome P450/endothelin-1 pathway[3]. By proteomic analysis, we compared patent and constricted human DA samples, finding 132 different expression proteins, among of which 3.15% were related to ion channels[5]. NCX1 has been shown to play a key role in regulating intracellular calcium levels in both heart and smooth muscle cells[6, 7]. DA closure occurs in two overlapping phases[10]: (1) functional closure of the lumen, characterized by DA smooth muscle constriction, in which cytosolic calcium concentration ([Ca2+ ]i) plays a pivotal role; and (2) anatomic occlusion of the lumen due to extensive neointimal thickening. We investigated whether NCX-1 participate DA functional and anatomic closure
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