Modulation of cytosolic and nuclear calcium in endocardial endothelium by endothelin-1. Modulation du calcium cytosolique et nucléaire par l'endothéline-1 au niveau de l'endothélium endocardique.

内皮素 1 对心内膜内皮细胞胞质和核钙的调节。

• 批准号: RGPIN-2017-05508
• 负责人: Jacques, Danielle
• 金额: $ 1.82万
• 依托单位: Université de Sherbrooke
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=743418
• 关键词: Modulation; cytosolic; nuclear; calcium; endocardial

Despite the extensive knowledge in cell physiology, biology and pharmacology of the heart, several changes of contracting heart cells' normal functioning did not permit to prevent or treat some heart diseases. Such a problem is due, in part, to our negligence at the anatomical level in considering that the heart is not only constituted of contracting cardiomyocytes. Our group reported for the first time that the cells covering the heart ventricular cavities play an important role in the regulation of heart function. Thus, these cells should be considered as a pharmacological target to restore the normal heart function. Therefore, it is extremely important to understand the normal physiological, biological and pharmacological characteristics of these heart cells, called endocardial endothelial cells (EECs), which secrete many cardioactive factors. In addition, our negligence is also due to the lack of consideration that receptors, channels, exchangers and pumps are not only be present at the cell membrane but can also be found at other membranes inside the cell such as those of the nucleus. Our work reported for the first time that the nucleus could be considered as a cell within the cell and it contains structures, similar to those of its host cell, that were called nuclear nuclear T-tubules (NTTs) and nucleoplasmic reticulum (NR). In addition, we demonstrated that the membranes of these nuclear structures do contain, as the plasma membrane, channels, exchangers, pumps and receptors including those activated by factors released by EECs such as endothelin-1 (ET-1). Therefore, it is extremely important to understand the EECs physiology, biology and pharmacology in order to better understand the normal heart function. In addition, it is important to understand the contribution of intracellular structures present in the nucleus, such as the NTTs, in order to better understand their contribution to EECs secretory function. Thus, our overall research program is to test the hypothesis that EECs are major contributors to normal heart function and that factors released by these cells such as ET-1 regulate, via activation of its receptors present at both the plasma, nuclear and NTT membranes. This research program will also help us to further support our major hypothesis that abnormal physiological function of EECs, and more particularly of NTTs' ET-1 receptors, is at the heart' of some abnormal heart problems.

尽管人们对心脏的细胞生理学、生物学和药理学有了广泛的了解，但收缩心脏细胞正常功能的一些变化并不能预防或治疗某些心脏病。这一问题的部分原因是我们在解剖学层面上的疏忽，没有考虑到心脏不仅由收缩的心肌细胞组成。我们课题组首次报道了覆盖心室腔的细胞在心脏功能的调节中发挥着重要作用。因此，这些细胞应被视为恢复正常心脏功能的药理学靶点。因此，了解这些心脏细胞（心内膜内皮细胞（EEC））的正常生理、生物和药理学特征极其重要，它们分泌许多心脏活性因子。此外，我们的疏忽还在于没有考虑到受体、通道、交换器和泵不仅存在于细胞膜上，而且还存在于细胞内的其他膜上，例如细胞核的膜上。我们的工作首次报道，细胞核可以被视为细胞内的细胞，它包含与其宿主细胞相似的结构，称为核核 T 管 (NTT) 和核质网 (NR)。此外，我们证明这些核结构的膜确实包含质膜、通道、交换器、泵和受体，包括由 EEC 释放的因子（如内皮素-1 (ET-1)）激活的受体。因此，了解EEC的生理、生物学和药理学对于更好地了解正常的心脏功能极为重要。此外，了解细胞核中存在的细胞内结构（例如 NTT）的贡献也很重要，以便更好地了解它们对 EEC 分泌功能的贡献。因此，我们的总体研究计划是检验以下假设：EEC 是正常心脏功能的主要贡献者，并且这些细胞释放的因子（例如 ET-1）通过激活质膜、核膜和 NTT 膜上的受体进行调节。这项研究计划还将帮助我们进一步支持我们的主要假设，即 EEC（尤其是 NTT 的 ET-1 受体）的异常生理功能是某些异常心脏问题的核心。