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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL089298-05
Application #
8293202
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
OH, Youngsuk
Project Start
2008-08-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$388,575
Indirect Cost
$141,075
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Wang, Hao; Zhou, Tiantian; Peng, Jianhao et al. (2015) Distinct roles of N-glycosylation at different sites of corin in cell membrane targeting and ectodomain shedding. J Biol Chem 290:1654-63
Theilig, Franziska; Wu, Qingyu (2015) ANP-induced signaling cascade and its implications in renal pathophysiology. Am J Physiol Renal Physiol 308:F1047-55
Chen, Shenghan; Cao, Pengxiu; Dong, Ningzheng et al. (2015) PCSK6-mediated corin activation is essential for normal blood pressure. Nat Med 21:1048-53
Zhou, Yiqing; Wu, Qingyu (2014) Corin in natriuretic peptide processing and hypertension. Curr Hypertens Rep 16:415
Dong, Ningzheng; Zhou, Tiantian; Zhang, Yue et al. (2014) Corin mutations K317E and S472G from preeclamptic patients alter zymogen activation and cell surface targeting. [Corrected]. J Biol Chem 289:17909-16
Zhang, Yue; Li, Hui; Zhou, Jianping et al. (2014) A corin variant identified in hypertensive patients that alters cytoplasmic tail and reduces cell surface expression and activity. Sci Rep 4:7378
Dong, Ningzheng; Fang, Chaodong; Jiang, Yizhi et al. (2013) Corin mutation R539C from hypertensive patients impairs zymogen activation and generates an inactive alternative ectodomain fragment. J Biol Chem 288:7867-74
Zhou, Y; Wu, Q (2013) Role of corin and atrial natriuretic peptide in preeclampsia. Placenta 34:89-94
Wang, Wei; Cui, Yujie; Shen, Jianzhong et al. (2012) Salt-sensitive hypertension and cardiac hypertrophy in transgenic mice expressing a corin variant identified in blacks. Hypertension 60:1352-8
Dong, Ningzheng; Chen, Shenghan; Wang, Wei et al. (2012) Corin in clinical laboratory diagnostics. Clin Chim Acta 413:378-83

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