REGULATION OF ANP RECEPTOR ACTIVITY IN VASCULAR CELLS

血管细胞中 ANP 受体活性的调节

• 批准号: 2222321
• 负责人: David G Gardner
• 金额: $ 19.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-07-01 至 1997-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2222321
• 关键词: DNA footprinting; atrial natriuretic peptide; cardiovascular function; gene expression; histochemistry /cytochemistry; homeostasis; hormone receptor; hormone regulation /control mechanism; hypertension; in situ hybridization; messenger RNA; peptide hormone biosynthesis; posttranslational modifications; receptor binding; tissue /cell culture; vascular smooth muscle

The atrial natriuretic peptide (ANP) is a peptide hormone which is synthesized, stored in and secreted from the cardiac atria. ANP binds to two different "receptor" forms on the surface of its target cells at the periphery. One form, the so-called "B-receptor", is ~ 130 kd in molecular weight, represents a small percentage of the total receptor population in most cell types and is linked to cGMP generation in the target cell. It is this receptor which is believed to mediate most of the known biological activities of ANP. The second receptor form, the so-called "C-receptor" is ~ 65 kd in molecular weight, is the predominant receptor present in most cell types and yet, despite its prevalence, its role as a bioeffector of ANP remains conjectural. On the basis of some intriguing whole animal studies this receptor has been postulated to play an important role in the clearance of ANP from circulating plasma. More recent studies suggest that this receptor may be coupled in a regulatory fashion to adenylate cyclase and/or phospholipase C activity in target cells. Preliminary evidence from our laboratory suggests that levels of the C- receptor on bovine vascular smooth muscle cells are reduced dramatically by treatment with cAMP-promoting agonists (e.g. forskolin, PGE2 or 8-BrcAMP). Additional studies, carried out with bovine aortic endothelial cells indicate that both ANP receptor subtypes are reduced by pretreatment with the phorbol ester TPA, thrombin or physical stretch of the cell monolayer. The proposed study will attempt: (1) to identify and characterize other factors which regulate either C or B receptor activity and their respective transcript mRNA's in cultured vascular cells and to determine how these various factors interact with one another; (2) to determine whether the acute effects of the regulatory factors identified are mediated by post- translational modification of the receptor protein(s); and (3) to identify and characterize the molecular determinants which govern the expression of the genes for each of the respective receptors. It is anticipated that information gained from these studies will yield a more accurate assessment of ANP's integrative role in modulating cardiovascular homeostasis and provide us with some insight into possible pathophysiological mechanisms whereby malregulation of ANP bioactivity could result in abnormalities of arterial blood pressure.

心房钠尿肽（ANP）是一种肽激素， 合成、储存于心房并由心房分泌。 ANP 结合 其靶细胞表面有两种不同的“受体”形式 周边。 一种形式，即所谓的“B 受体”，分子大小约为 130 kd 重量，代表受体总数的一小部分 大多数细胞类型，并与靶细胞中 cGMP 的生成有关。 这是 这种受体被认为介导大多数已知的生物 ANP 的活动。 第二种受体形式，所谓的“C受体”是 分子量约为 65 kd，是大多数细胞中存在的主要受体 细胞类型，尽管它很普遍，但它作为生物效应器的作用 ANP 仍然是推测性的。 以一些有趣的整体动物为基础 研究认为该受体在 从循环血浆中清除 ANP。 最近的更多研究表明 该受体可能以调节方式与腺苷酸环化酶偶联 和/或靶细胞中磷脂酶 C 的活性。 我们实验室的初步证据表明，C-的水平 牛血管平滑肌细胞上的受体显着减少 使用 cAMP 促进激动剂（例如毛喉素、PGE2 或 8-BrcAMP）治疗。 使用牛主动脉内皮细胞进行的其他研究 表明两种 ANP 受体亚型均通过预处理而减少 佛波酯 TPA、凝血酶或细胞单层的物理拉伸。 拟议的研究将尝试：（1）识别和描述其他 调节 C 或 B 受体活性的因素及其各自 在培养的血管细胞中转录 mRNA 并确定这些 各种因素相互作用； (2)判断是否 所确定的调节因素的急性影响是由后调节因素介导的 受体蛋白的翻译修饰； (3) 识别 并表征控制表达的分子决定因素 每个受体的基因。 预计 从这些研究中获得的信息将产生更准确的评估 ANP 在调节心血管稳态中的综合作用 为我们提供一些可能的病理生理机制的见解 ANP 生物活性的失调可能导致 动脉血压。