Hypertension is the most common cardiovascular disease, afflicting nearly one in every three American adults. The underlying disease mechanism in hypertension is not well understood. Atrial natriuretic peptide (ANP) is a cardiac hormone, which promotes sodium and water excretion and decreases peripheral vascular tension, thereby lowering blood volume and pressure. In cardiac myocytes, ANP is synthesized as a precursor, pro-ANP, which is activated to ANP by the cell membrane serine protease, corin, which we discovered in the heart. In mice, lack of corin abolishes pro-ANP activation. Corin knockout mice develop salt-sensitive hypertension and cardiac hypertrophy. In humans, corin variants and mutations have been identified in patients with hypertension and cardiac hypertrophy. We showed that the corin variants and mutants had impaired pro-ANP processing activity. Transgenic mice expressing corin variants developed salt-sensitive hypertension and cardiac hypertrophy. As a serine protease, corin is made as an inactive zymogen, which is activated by proteolytic cleavage. To date, the corin activator remains elusive. Recent studies indicate that impaired corin zymogen activation plays a critical role in hypertension and heart disease, highlighting the importance of studying corin activation. In this proposal, we plan to study the mechanism underlying corin activation.
In Aim 1, we will determine cellular mechanism underlying corin activation.
In Aim 2, we will identify structural elements important for corin biosynthesis and zymogen activation.
In Aim 3, we will examine corin activation, pro-ANP processing and blood pressure in knockout mouse models. Our studies should provide new insights into the mechanism controlling corin activity and potential implication of impaired corin activation in hypertensive disease.

Public Health Relevance

High blood pressure, also called hypertension, is a common disease that can cause stroke and heart attack. To date, the cause of the disease remains unclear. Recently, we found a novel protein, corin, in the heart that is important in maintaining normal blood pressure. In this study, we plan to analyze corin function and understand its role in hypertension and heart disease. Our goal is 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 #
5R01HL126697-04
Application #
9438920
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
OH, Youngsuk
Project Start
2015-04-08
Project End
2019-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Li, Hui; Zhang, Yue; Wu, Qingyu (2017) Role of corin in the regulation of blood pressure. Curr Opin Nephrol Hypertens 26:67-73
Zhang, Yue; Zhou, Tiantian; Niu, Yayan et al. (2017) Identification and functional analysis of CORIN variants in hypertensive patients. Hum Mutat 38:1700-1710
Li, Hui; Zhang, Yue; Wang, Lina et al. (2015) A novel cytoplasmic tail motif regulates mouse corin expression on the cell surface. Biochem Biophys Res Commun 465:152-8
Chen, Shenghan; Cao, Pengxiu; Dong, Ningzheng et al. (2015) PCSK6-mediated corin activation is essential for normal blood pressure. Nat Med 21:1048-53
Song, Wei; Wang, Hao; Wu, Qingyu (2015) Atrial natriuretic peptide in cardiovascular biology and disease (NPPA). Gene 569:1-6