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）：高血压或高血压是最普遍的心血管疾病，每三个美国成年人中几乎都会受苦。在非裔美国人中，这种疾病的患病率甚至更高，但根本原因尚不清楚。心房尿肽（ANP）是心激素。当血压升高时，ANP会从心脏中释放出来，以促进肾脏钠和水排泄并降低外周血管张力，从而降低血压。在心肌细胞中，ANP是前体，Pro-ANP，该前体被蛋白水解酶激活为ANP。该激活步骤对于调节ANP活性至关重要，但是加工酶在多年内仍然难以捉摸。最近，我们发现了一种心脏丝氨酸蛋白酶科林。我们表明科林以序列特异性方式激活了pro-ANP。我们制作了无缺陷的小鼠，其中取消了AR-ANP激活，这表明Corin是生理pro-ANP转化酶。科林缺陷小鼠会出现高盐饮食加剧的高血压，这表明科林对于维持正常的血压至关重要。科林还在体外裂解了pro-b型亚替肽肽（BNP）。最近，发现科林基因中的非同义单核苷酸多态性（SNP）与非裔美国人的高血压和心脏肥大有关。在此提案中，我们将检验以下假设：SNP改变了科林的功能并导致高血压和心脏病。在AIM 1中，我们将在生化和基于细胞的测定中研究Corin及其在Pro-ANP和Pro-BNP加工中的变体。在AIM 2中，我们将检查Corin激活中的分子机制。在AIM 3中，我们将确定Corin及其变体在小鼠模型中在纳地尿肽加工，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起作用。我们的研究可能有助于设计新策略，以诊断和治疗患有高血压和心力衰竭的患者。公共卫生相关性：几乎每三分之一的美国成年人都会出现高血压，也称为高血压，这种疾病可能引起中风和心脏病发作。在非裔美国人中，这种疾病比普通人群更为普遍，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，这对于保持正常血压很重要。最近，在具有高血压和心脏病的非裔美国人中发现了Corin基因变体。在这项研究中，我们将进行实验，以找出科林基因是否改变会导致血压和心脏问题。我们的工作将有助于开发新的方法来诊断和治疗高血压和心脏病的患者。