The cardiac protease corin in natriuretic peptide processing and hypertension

心脏蛋白酶corin在利尿钠肽加工和高血压中的作用

• 批准号: 7841249
• 负责人: Qingyu Wu
• 金额: $ 28.7万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7841249
• 关键词: Adult; Affect; African American; Alleles; American; Amino Acids; Atrial Natriuretic Factor; Biochemical; Biological Assay; Blood Pressure; Blood Vessels; Blood Volume; Brain natriuretic peptide; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cells; Cleaved cell; Cysteine Protease; Data; Defect; Diagnosis; Diet; Disease; Enzyme Precursors; Enzymes; Excretory function; Exhibits; Family member; General Population; Genes; Genetic Variation; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Hormones; Human; Hypertension; Hypotension; In Vitro; Kidney; Knockout Mice; Left Ventricular Mass; Matrix Metalloproteinase Inhibitor; Measures; Molecular; Mus; Myocardial Infarction; Natriuretic Peptides; Pathway interactions; Patients; Peptide Hydrolases; Peripheral; Phenotype; Physiological; Play; Pre-Eclampsia; Pregnancy; Prevalence; Process; Proprotein Convertases; Proteins; Proteinuria; RNA Interference; Regulation; Risk; Role; Serine Protease; Serine Proteinase Inhibitors; Single Nucleotide Polymorphism; Sodium; Sodium Chloride; Stroke; Testing; Transgenes; Transgenic Organisms; Variant; Water; Work; base; blood pressure regulation; design; human disease; hypertensive heart disease; in vivo; mouse model; mutant; overexpression; pressure; prolyl-proline; promoter; public health relevance; receptor; research study; response; salt sensitive

DESCRIPTION (provided by applicant): Hypertension, or high blood pressure, is the most prevalent cardiovascular disease, afflicting nearly one in every three American adults. The prevalence of this disease is even higher in African-Americans but the underlying cause is unknown. Atrial natriuretic peptide (ANP) is a cardiac hormone. When blood pressure increases, ANP is released from the heart to promote renal sodium and water excretion and decrease peripheral vascular tension, thereby lowering blood pressure. In cardiomyocytes, ANP is made as a precursor, pro-ANP, which is activated to ANP by a proteolytic enzyme. This activation step is critical in regulating ANP activity but the processing enzyme remained elusive for many years. Recently, we discovered a cardiac serine protease, corin. We showed that corin activated pro-ANP in a sequence-specific manner. We made corin-deficient mice in which pro-ANP activation was abolished, demonstrating that corin is the physiological pro-ANP convertase. Corin-deficient mice develop hypertension that was exacerbated by a high-salt diet, indicating that corin is essential in maintaining normal blood pressure. Corin also cleaved pro-B-type natriuretic peptide (BNP) in vitro. Most recently, non- synonymous single nucleotide polymorphisms (SNPs) in the corin gene are found to be associated with hypertension and cardiac hypertrophy in African-Americans. In this proposal, we will test the hypothesis that the SNPs alter corin function and contribute to hypertensive and heart disease. In Aim 1, we will examine corin and its variants in pro-ANP and pro-BNP processing in biochemical and cell-based assays. In Aim 2, we will examine the molecular mechanism in corin activation. In Aim 3, we will determine the role of corin and its variants in natriuretic peptide processing, blood pressure regulation, and cardiac hypertrophy in mouse models. Our studies will help to elucidate the function and regulation of this newly-discovered enzyme and, more importantly, to understand if corn deficiency plays a role in hypertensive and heart disease. Our studies may help to design new strategies to diagnose and treat patients with hypertension and heart failure. PUBLIC HEALTH RELEVANCE: Nearly one in every three American adults develops high blood pressure, also called hypertension, a disease that can cause stroke and heart attack. This disease is even more common in African-Americans than in the general population, but the exact cause is not known. We discovered a new protein, corin, from the heart that is important in keeping normal blood pressure. Recently, corin gene variants are found in African-Americans with high blood pressure and heart disease. In this study, we will do experiments to figure out if corin gene changes cause blood pressure and heart problems. Our work will help to develop new ways to diagnose and treat patients with high blood pressure and heart disease.

描述（由申请人提供）：高血压是最常见的心血管疾病，近三分之一的美国成年人患有高血压。这种疾病在非裔美国人中的患病率更高，但根本原因尚不清楚。心房钠尿肽（ANP）是一种心脏激素。当血压升高时，心脏释放ANP，促进肾钠、水排泄，降低外周血管张力，从而降低血压。在心肌细胞中，ANP 是作为前体 ANP 前体产生的，ANP 前体被蛋白水解酶激活为 ANP。这一激活步骤对于调节 ANP 活性至关重要，但多年来加工酶仍然难以捉摸。最近，我们发现了一种心脏丝氨酸蛋白酶，corin。我们证明 Corin 以序列特异性方式激活 ANP 前体。我们制作了 corin 缺陷小鼠，其中 pro-ANP 激活被消除，证明 corin 是生理学的 pro-ANP 转化酶。缺乏 Corin 的小鼠会出现高血压，高盐饮食会加剧高血压，这表明 Corin 对于维持正常血压至关重要。 Corin 还在体外裂解 B 型钠尿肽原 (BNP)。最近，corin 基因中的非同义单核苷酸多态性 (SNP) 被发现与非裔美国人的高血压和心脏肥大有关。在本提案中，我们将检验 SNP 改变 corin 功能并导致高血压和心脏病的假设。在目标 1 中，我们将在生化和细胞检测中检查 corin 及其变体在 pro-ANP 和 pro-BNP 加工中的作用。在目标 2 中，我们将研究 corin 激活的分子机制。在目标 3 中，我们将确定 corin 及其变体在小鼠模型中利钠肽加工、血压调节和心脏肥大中的作用。我们的研究将有助于阐明这种新发现的酶的功能和调节，更重要的是，了解玉米缺乏症是否与高血压和心脏病有关。我们的研究可能有助于设计新的策略来诊断和治疗高血压和心力衰竭患者。公共卫生相关性：近三分之一的美国成年人患有高血压，也称为高血压，这是一种可导致中风和心脏病的疾病。这种疾病在非裔美国人中比在普通人群中更为常见，但确切原因尚不清楚。我们发现了一种来自心脏的新蛋白质，corin，它对于保持正常血压很重要。最近，在患有高血压和心脏病的非裔美国人中发现了corin基因变异。在这项研究中，我们将进行实验来弄清楚corin基因的变化是否会导致血压和心脏问题。我们的工作将有助于开发诊断和治疗高血压和心脏病患者的新方法。