S-nitrosothiol signaling in pulmonary epithelial cells

肺上皮细胞中的 S-亚硝基硫醇信号传导

• 批准号: 8577192
• 负责人: Lisa A Palmer
• 金额: $ 23.91万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8577192
• 关键词: Address; Affect; Air; Androgens; Asthma; Biological Availability; Biology; Blood Vessels; Cilia; Coupling; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Development; Disease; Dissociation; Endoplasmic Reticulum; Endothelial Cells; Endothelium; Epithelial; Epithelial Cells; Epithelium; Esters; Estrogens; Feedback; Female; Gender; Heat-Shock Proteins 90; Hormones; Human; Humulus; In Vitro; Knowledge; Lead; Liquid substance; Location; Lung; Lung diseases; Mediating; Mus; Nitric Oxide Synthase; Oxidoreductase; Pathology; Physiology; Play; Predisposition; Protein S; Proteins; Puberty; Pulmonary Hypertension; Regulation; Risk; Role; S-Nitrosoglutathione; S-Nitrosothiols; Severities; Signal Pathway; Signal Transduction; Stress; Testing; Therapeutic Agents; Toxic effect; Ubiquitination; Up-Regulation; Vascular Diseases; Vascular Endothelium; Vascular remodeling; airway epithelium; base; cystic fibrosis airway epithelia; gender preference; genetic regulatory protein; hormone regulation; human NOS3 protein; in vivo; male; new therapeutic target; novel; respiratory

The current proposal identifies a novel hormonally regulated S-nitrosylation/denitrosylation coupling loop in the pulmonary vascular endothelium. This feedback loop consists of eNOS, which is up-regulated by estrogens, and GSNO-R, which is down-regulated by androgens. These two proteins physically interact, however the impact of this interaction on pulmonary physiology and pathology is unknown. Thus, defining the subcellular location of this interaction within the endothelial cell and the influence of this relationship on local S-nitrosothiol (SNO) abundance is of paramount importance to identifying its role in normal pulmonary vascular physiology and pathology. SNOs have been implicated in the development of various pulmonary diseases, many of which display distinct gender preferences in presentation or a change in severity at puberty by unknown mechanisms. In this respect, estrogen increases SNO formation causing a compensatory increase in GSNO-R activity. Thus, increased pulmonary vascular endothelial SNO exposure without increases in GSNO-R activity, which is abnormal in male mice exposed to exogenous SNOs, produces SNO toxicity including pulmonary vascular remodeling and PH. Thus, abnormalities in GSNO-R may diminish protection of pulmonary vascular endothelium to increased eNOS activity, resulting in increased risk to develop PH. We hypothesize that SNO bioavailability in the endothelium is regulated by a hormonally regulated S-nitrosylation/denitrosylation coupling loop. This regulatory loop may be involved in the regulation of eNOS activity and SNO bioavailability within the vascular endothelium Moreover, disruption of this regulatory loop plays a role in the gender divergence seen in PH. Three hypotheses will be examined. Aim 1: GSNO-R and eNOS crosstalk exists within the pulmonary endothelium. Aim 2: Subcellular location of eNOS/GSNO-R interaction contributes to local SNO bioavailability. Aim 3: Disruption of this S-nitrosylation/denitrosylation regulatory loop contributes to the gender discordance seen in PH. In summary, defining the importance of the hormonal regulation of this coupling loop and its relationship to gender susceptibility of pulmonary vascular disease will enhance our knowledge on the mechanisms of male/female mediated susceptibility/protection to disease and will increase the potential to develop gender specific therapeutic agents.

本研究发现在肺血管内皮细胞中存在一种新的受激素调节的S-亚硝化/反硝化偶联环路。这个反馈环由雌激素上调的eNOS和雄激素下调的GSNO-R组成。这两种蛋白质在物理上相互作用，但这种相互作用对肺生理和病理的影响尚不清楚。因此，定义这种相互作用在内皮细胞内的亚细胞位置以及这种关系对 局部的S-亚硝硫醇(SNO)含量对于确定其在正常肺血管生理和病理中的作用是至关重要的。SNO与各种肺部疾病的发展有关，其中许多疾病在表现上表现出明显的性别偏好，或者在青春期以未知的机制改变严重程度。在这方面，雌激素增加了SNO的形成，导致GSNO-R活性的代偿性增加。因此，肺血管内皮细胞SNO暴露增加 如果GSNO-R活性不增加，这在暴露于外源性SNO的雄性小鼠中是异常的，则会产生SNO毒性，包括肺血管重构和PH。因此，GSNO-R的异常可能会减弱肺血管内皮细胞对eNOS活性增加的保护，从而增加发生PH的风险。我们假设SNO在内皮细胞中的生物利用度受激素调节的S-亚硝化/反亚硝化偶联环路调节。这一监管环路可能是 参与血管内皮细胞内eNOS活性和SNO生物利用度的调节此外，这一调节环路的破坏在PH患者的性别差异中发挥了作用。我们将检验三个假设。 目的1：肺内皮细胞内存在GSNO-R和eNOS的串扰。 目的2：eNOS/GSNO-R相互作用的亚细胞定位有助于局部SNO的生物利用度。 目的3：这种S-亚硝化/反硝化调节环路的破坏是导致PH患者性别差异的原因之一。 总之，明确这种偶联环路荷尔蒙调节的重要性及其与肺血管疾病性别易感性的关系将加强我们对男性/女性介导的疾病易感性/保护机制的了解，并将增加发展性别的潜力。 特定的治疗剂。