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  • Evidence for interactions between the endothelin and the ang

    2019-07-18

    Evidence for interactions between the endothelin and the angiotensin system has also become plentiful. It has become clear that the two systems, in addition to acting independently, can act synergistically (Emori et al., 1989, Imai et al., 1992) as well as promote the peptide mRNA expression in endothelial cells (ECs) from various origins such as heart, ursolic acid and resistance vessels of mesenteric arteries (Chua et al., 1993). Most of the literature in the field of endothelial cells focuses on the vascular endothelial cells, however, less information is available about the endothelial cells that cover the cardiac cavities which contribute to direct regulation of the level and tuning of circulating peptides (Brutsaert, 2003). The latter type of cells also directly contributes to heart function. In addition, the sub-endocardial nerve plexus is known to release NPY (Marron et al., 1994) which regulates the endocardial endothelial cell secretory function (Abdel-Samad et al., 2012). Moreover, differences in excitation-secretion coupling exist between human right and left ventricular endocardial endothelial cells (hREECs and hLEECs respectively) (Jacques et al., 2005, Jules et al., 2015). Recently, our group showed that NPY induced a release of ET-1 in both hREECs and hLEECs and this effect was mediated by activation of NPY receptors (Abdel-Samad et al., 2012). Although NPY promotes the release of ET-1 in human ventricular endocardial endothelial cells (hEECs) (Abdel-Samad et al., 2012), the latter peptide attenuates the release of NPY upon high frequency nerve stimulation which was mediated via ETB receptor activation (Hoang et al., 2002). However, it is unknown whether the ET-1 secretion induced by NPY concomitantly contributes to upregulation of its own secretion via activation of its receptors ETA or ETB. Thus, the aim of this study is to investigate whether the secreted ET-1 due to NPY stimulation of hEECs contributes to its own release via activation of the ETA and/or ETB receptor(s) and whether this depends on hEEC type.
    Materials and methods
    Results
    Discussion In this study, we demonstrated that, at the level of hREECs, blockade of the ETA receptor partially inhibited the effect of NPY on the secretion of ET-1. This suggests that the secreted ET-1 by NPY contributes, in part, to its own secretion via activation of the ETA receptor. However, Y2 receptor blockade completely inhibited the NPY-induced release of ET-1 in hREECs (Abdel-Samad et al., 2012), whereas ETA receptor blockade partially inhibited this release. Therefore, it can be suggested that a part of the Y2-mediated effect on the secretion of ET-1 in hREECs is due to the released ET-1-mediated activation of the ETA receptor. Blockade of the ETB receptor followed by stimulation of hREECs with NPY was able to abolish the release of ET-1 from these cells, suggesting the contribution of the ET-1 released by NPY to its own secretion not only by activation of the ETA receptor, but by activation of the ETB receptor as well. On the other hand, and in contrast to what was observed in hREECs, neither blockade of the ETA nor blockade of the ETB receptor had any effect on the NPY-induced release of ET-1 in hLEECs. It seems therefore, that the ET-1 secreted as a result of hLEEC stimulation with NPY is not contributing to its own further release. It is possible that the presence of an effect for the ETA and ETB receptor antagonists on the NPY-induced release of ET-1 at the level of hREECs is due to the high capacity of ET-1 secretion that this type of cells possesses (Abdel-Samad et al., 2012). In other words, the level of ET-1 secreted by hREECs as a result of NPY stimulation seems to be sufficient to activate the ETA and ETB receptors on these cells resulting in their contribution in part to the NPY-induced-ET-1-stimulated-ET-1 release. However, the absence of an effect of both the ETA and ETB receptor antagonists on the NPY-induced ET-1 secretion from hLEECs could perhaps be explained by the lower ET-1 secretory capacity of these cells when compared to hREECs (Abdel-Samad et al., 2012). In other words, and by analogy to what was said above for hREECs, the level of ET-1 secreted by hLEECs as a result of NPY stimulation does not seem to be sufficient to activate the ETA or ETB receptors.