Regulation of nuclear calcium and ROS by Angiotensin II in heart cells. Régulation du calcium et ROS nucléaires par l'angiotensine II dans les cellules cardiaques.

血管紧张素 II 对心脏细胞中核钙和 ROS 的调节。

• 批准号: RGPIN-2016-04414
• 负责人: Bkaily, Ghassan
• 金额: $ 2.04万
• 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=743412
• 关键词: Regulation; nuclear; calcium; ROS; Angiotensin

Recent work from our laboratory led us to our general hypothesis that the nucleus is a cell within a cell. Our early work opened a new field that helped to better understand cell physiology and biology. The progress in this new field, including that of our laboratory showed that, similarly to a cell, the nucleus possesses membranes that contain proteins such as ionic channels, ionic transporters and G-protein coupled receptors (GPCRs). These latter are activated by their respective bioactive factors present inside the cells such as angiotensin II (Ang II). In addition, our recent work showed that, as a cell, the nucleus does possess intranuclear structures, similar to those of the cell membrane, such as those called by our group nuclear T-tubules and nucleoplasmic reticulum. All of these nuclear structures and membrane proteins work together with those of the cell membrane in order to supply the nucleus with its needs, thus enabling it to achieve its important role in the regulation of normal cell function. In addition, the nucleus can act independently of its cell to supply itself by the factors that are needed to achieve its role. Ang II, a circulating active octopeptide, is known to affect the function of heart cells during embryonic development and growth. The receptor proteins known to be stimulated by this hormone are present in the cell membrane. However, our work showed that these Ang II receptors are also present in nuclear membranes and may contribute to the regulation and control of contraction of heart cells. This is done via the contribution of the nucleus to cytosolic and nuclear regulation of calcium level which is responsible for cardiac cell contraction. Calcium level is also known to be implicated in both the life and death of the cell. Furthermore, our recent published work from our laboratory (was granted by NSERC) showed that activation of either cell membrane and/or nuclear membranes Ang II receptors in vascular smooth muscle cells and heart cells induced generation of cytosolic and nuclear oxidants (ROS). However, the possibility that the activation of nuclear membranes Ang II receptors modulating oxidative stress, which in turn would or might affect nuclear calcium and cell function, remains to be explored.This project will help us to better understand the role of Ang II in generating oxidative stress and regulating the level of both cytosolic and nuclear Ca2+. The level of this latter ion is known to regulate heart cell contractions as well as heart development and aging.

我们实验室最近的工作使我们得出了一个普遍的假设，即细胞核是细胞中的细胞。我们的早期工作开辟了一个新的领域，有助于更好地理解细胞生理学和生物学。这一新领域的进展，包括我们实验室的进展表明，与细胞类似，细胞核具有含有蛋白质的膜，如离子通道，离子转运蛋白和G蛋白偶联受体（GPCR）。后者由细胞内存在的各自的生物活性因子如血管紧张素II（Ang II）激活。此外，我们最近的工作表明，作为一个细胞，细胞核确实具有核内结构，类似于细胞膜的结构，例如我们小组称为核T-小管和核质网的结构。所有这些核结构和膜蛋白与细胞膜的结构和膜蛋白一起工作，以便为核提供所需，从而使其能够在正常细胞功能的调节中发挥重要作用。此外，细胞核可以独立于其细胞发挥作用，为自己提供实现其作用所需的因子。血管紧张素II是一种循环活性八肽，已知在胚胎发育和生长期间影响心脏细胞的功能。已知受这种激素刺激的受体蛋白存在于细胞膜中。然而，我们的工作表明，这些血管紧张素II受体也存在于核膜，并可能有助于调节和控制心脏细胞的收缩。这是通过细胞核对负责心脏细胞收缩的钙水平的胞质和核调节的贡献来完成的。钙水平也被认为与细胞的生命和死亡有关。此外，我们实验室最近发表的工作（由NSERC授予）表明，血管平滑肌细胞和心脏细胞中的细胞膜和/或核膜Ang II受体的激活诱导细胞溶质和核氧化剂（ROS）的产生。然而，是否通过激活核膜Ang Ⅱ受体来调节氧化应激，进而影响核内钙离子浓度和细胞功能，这一研究结果将有助于我们更好地理解Ang Ⅱ在氧化应激中的作用以及对胞浆和核内钙离子水平的调节。后一种离子的水平已知可以调节心脏细胞收缩以及心脏发育和衰老。