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.

心房亚催化肽（ANP）是一种肽激素，是 合成，存储在心脏中心中并分泌。 ANP与 其目标细胞表面的两种不同的“受体”形式 周边。 一种形式，即所谓的“ B受体”，分子的形式约为130 kd 重量，占总受体人群的一小部分 大多数细胞类型，并链接到目标细胞中的CGMP生成。 这是 据信这种受体介导了大多数已知的生物学 ANP的活动。 第二个受体形式，所谓的“ C受体”是 分子量的〜65 kd是大多数存在的主要受体 细胞类型，但尽管率很高，但其作用是 ANP仍然是猜想。 基于一些有趣的全动物 研究该受体已被认为在 从循环血浆中清除ANP。 最近的研究表明 该受体可以以调节方式与腺苷酸环化酶结合 靶细胞中的磷脂酶C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大大降低 用营地促进激动剂（例如Forskolin，PGE2或8-Brcamp）进行治疗。 用牛主动脉内皮细胞进行的其他研究 表明两种ANP受体亚型都通过对 细胞单层的Phorbol酯TPA，凝血酶或物理拉伸。 拟议的研究将尝试：（1）识别和表征其他 调节C或B受体活性及其各自的因素 在培养的血管细胞中的转录物mRNA，并确定如何 各种因素相互作用； （2）确定是否 鉴定的调节因素的急性影响是通过后介导的 受体蛋白的翻译修饰； （3）确定 并表征控制的分子决定因素 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在调节心血管稳态和 为我们提供一些对可能的病理生理机制的见解 因此，ANP生物活性的破坏可能导致异常 动脉血压。