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: 8107536
• 负责人: Qingyu Wu
• 金额: $ 39.25万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8107536
• 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; Health; 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 Mice; Variant; Water; Work; base; blood pressure regulation; design; human disease; hypertensive heart disease; in vivo; mouse model; mutant; overexpression; promoter; 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）：高血压是最普遍的心血管疾病，几乎每三个美国成年人中就有一个患有高血压。这种疾病的患病率在非洲裔美国人中甚至更高，但根本原因尚不清楚。心房利钠肽（ANP）是一种心脏激素。当血压升高时，心钠素从心脏释放，促进肾脏钠和水的排泄，降低外周血管张力，从而降低血压。在心肌细胞中，ANP作为前体产生，前ANP通过蛋白水解酶活化为ANP。这个激活步骤在调节ANP活性中是至关重要的，但加工酶多年来一直难以捉摸。最近，我们发现了一种心脏丝氨酸蛋白酶corin。我们发现，corin激活前心钠素在一个序列特异性的方式。我们制作了corin缺陷小鼠，其中pro-ANP激活被消除，证明corin是生理性pro-ANP转化酶。corin缺乏的老鼠会患上高血压，而高盐饮食会加剧这种高血压，这表明corin在维持正常血压方面是必不可少的。Corin还在体外切割前B型利钠肽（BNP）。最近，corin基因中的非同义单核苷酸多态性（SNP）被发现与非洲裔美国人的高血压和心脏肥大相关。在这个提议中，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研究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的利钠肽加工、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，了解玉米缺乏是否在高血压和心脏病中发挥作用。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。公共卫生关系：近三分之一的美国成年人患有高血压，也称为高血压，一种可导致中风和心脏病发作的疾病。这种疾病在非洲裔美国人中比在普通人群中更常见，但确切的原因尚不清楚。我们从心脏中发现了一种新的蛋白质corin，它对保持正常血压很重要。最近，在患有高血压和心脏病的非洲裔美国人中发现了corin基因变异。在这项研究中，我们将做实验来弄清楚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。