 |
Qingyu Wu, M.D., Ph.D.Staff
Department of Molecular Cardiology
|
Proteolytic enzymes in the cardiovascular system.
High blood pressure, also called hypertension, increases the risk for major cardiovascular diseases such as myocardial infarction, stroke, heart failure, and kidney failure. Corin is a serine protease we discovered in the heart. Corin converts pro-atrial natriuretic peptide (ANP) to active ANP, a cardiac hormone essential for maintaining normal blood pressure.
In mice, corin deficiency prevents this pro-ANP to ANP conversion and causes hypertension, demonstrating the importance of corin in producing ANP and controlling blood pressure in vivo. In humans, single nucleotide polymorphisms (SNPs) in the corin gene are associated with an increased risk for hypertension and cardiac hypertrophy in African-Americans.
In functional studies, we found that corin variants caused by SNPs had a low biological activity, suggesting that genetic variants may impair corin function and contribute to hypertension and heart disease in patients.
We use biochemical tools to study the regulation of corin function. We also develop animal models to understand the role of corin in cardiovascular disease.
Yan W, Sheng N, Seto M, Morser J, Wu Q: Corin: a mosaic transmembrane serine protease encoded by a novel cDNA from human heart. J. Biol. Chem. 1999;274:14926-14935.
Yan W, Wu F, Morser J, Wu Q: Corin, a transmembrane cardiac serine protease, acts as a pro-atrial natriuretic peptide converting enzyme. Proc. Natl. Acad. Sci. USA 2000;97:8525-8529.
Wu F, Yan W, Pan J, Morser J, Wu Q: Processing of pro-atrial natriuretic peptide by corin in cardiac myocytes. J. Biol. Chem. 2002;277:16900-16905.
Pan J, Hinzmann B, Yan W, Wu F, Morser J, Wu Q: Genomic structures of the human and murine corin genes and functional GATA elements in their promoters. J. Biol. Chem. 2002;277:38390-38398.
Wu Q: Type II transmembrane serine proteases. Curr. Top. Dev. Biol. 2003;54:167-206.
Knappe S, Wu F, Masikat MR, Morser J, Wu Q: Functional analysis of the transmembrane domain and activation cleavage of human corin: design and characterization of a soluble corin. J. Biol. Chem. 2003;278:52363-52370.
Wu C, Wu F, Pan J, Morser J, Wu Q: Furin-mediated processing of pro-C-type natriuretic peptide J. Biol. Chem. 2003;278:25847-25852.
Wu F, Wu Q: Corin-mediated processing of pro-atrial natriuretic peptide in human small cell lung cancer cells. Cancer Res. 2003;63:8318-8322.
Knappe S, Wu F, Madlansacay MR, Wu Q: Identification of domain structures in the propeptide of corin essential for the processing of pro-atrial natriuretic peptide. J. Biol. Chem. 2004;279:34464-34471.
Tran KL, Lu X, Lei M, Feng Q, Wu Q: Upregulation of corin gene expression in hypertrophic cardiomyocytes and failing myocardium. Am. J. Physiol. 2004:287:H1625-H1631.
Chan J, Knudson O, Wu F, Morser J, Dole WP, Wu Q: Hypertension in mice lacking the pro-atrial natriuretic peptide convertase, corin. Proc. Natl. Acad. Sci. USA 2005;102:785-790.
Dries DL, Victor R, Rame EJ, Cooper RS, Wu X, Zhu X, Leonard D, Ho SI, Wu Q, Post W, Drazner MH: Corin gene minor allele defined by 2 missense mutations is common in blacks and associated with high blood pressure and hypertension. Circulation 2005;112:2403-2410.
Xuan JA, Schneider D, Toy P, Lin R, Newton A, Zhu Y, Finster S, Vogel D, Mintzer B, Dinter H, Light D, Parry R, Polokoff M, Whitlow M, Wu Q, Parry G: Antibodies neutralizing hepsin protease activity do not impact cell growth but inhibit invasion of prostate and ovarian tumor cells in culture. Cancer Res. 2006;66:3611-3619. PMID: 16585186
Guipponi M, Tan J, Cannon P, Donley L, Crewther P, Clarke M, Wu Q, Shepherd RK, Scott HS: Mice deficient for the type II transmembrane serine protease, TMPRSS1/hepsin, exhibit profound hearing loss. Am. J. Path. 2007;171:608-616. PMID: 17620368
Liao X, Wang W, Chen S, Wu Q: Role of glycosylation in corin zymogen activation. J. Biol. Chem. 2007;282:27728-27735. PMID: 17660514
Wu Q. The serine protease corin in cardiovascular biology and disease. Front Biosci 2007;12:4179-4190. PMID: 17485366
Wang W, Liao X, Fukuda K, Knappe S, Wu F, Dries DL, Qin J, Wu Q: Corin variant associated with hypertension and cardiac hypertrophy exhibits impaired zymogen activation and natriuretic peptide processing activity. Circ. Res. 2008;103:502-508. PMID: 18669922
Wu Q, Xu-Cai YO, Chen S, Wang W: Corin: new insights into the natriuretic peptide system. Kidney Int. 2009;75:142-146. PMID: 18716602
Bugge T, Antalis T, Wu Q: Type II transmembrane serine proteases. J. Biol. Chem. 2009;284:23177-81. PMID: 19487698
Cui Y, Wu Q, Zhou Y: Iron-refractory iron deficiency anemia: new molecular mechanisms. Kidney International 2009;76:1137-1141. PMID: 19776721
Dong N, Chen S, Yang J, He L, Liu P, Zheng D, Li L, Zhou Y, Ruan C, Plow E, Wu Q: Plasma soluble corin in patients with heart failure. Circulation: Heart Failure 2010;3:207-211. PMID: 20061521
Jiang J, Pristera N, Wang W, Zhang X, Wu Q: Effect of sialylated O-glycans in pro-brain natruretic peptide stability. Clinical Chemistry 2010;56:959-966. PMID: 20348402
Caen J, Wu Q: Hageman factor, platelets and polyphosphates: early history and recent connection. J. Thromb. Haemostasis 2010;8:1670-1674. PMID: 20456750
Chen S, Sen S, Young D, Wang W, Moravec CS, Wu Q: Protease corin expression and activity in failing hearts. Am J Physiol Heart Circ 2010;299:H1687-H1692. PMID: 20802129
Naga Prasad SV, Duan ZH, Kumar S, Volinia S, Calin GA, Kotwal A, Moravec CS, Starling RC, Perez DM, Sen S, Wu Q, Plow E, Croce CM, Karnik S: A unique microRNA profile in end-stage heart failure indicates alterations in specific cardiovascular signaling networks. J. Biol. Chem. 2009;284:27487-99. PMID: 19641226
Xu-Cai YO, Wu Q: Molecular forms of natriuretic peptides in heart failure and their implications. Heart 2010;96:419-424. PMID: 19451138
Polzin P, Kaminski H, Kastner C, Wang W, Kramer S, Gambaryan S, Russwurm M, Peters H, Wu Q, Vandwalle A, Bachmann S, Theilig F: Decreased renal corin expression contributes to sodium retention in proteinuric kidney diseases. Kidney International 2010;78:660-667. PMID: 20613715
Shen J, Wu Q: Corin: a serine protease. Kidney International 2011;79:138-139. PMID: 21157466
Antalis TM, Bugge T, Wu Q: Membrane-anchored serine proteases in health and disease. Prog. Mol. Biol. Transl. Sci. 2011;99:1-50. PMID: 21238933
Jiang J, Wu S, Wang W, Chen S, Peng J, Zhang X, Wu Q: Ectodomain shedding and autocleavage of the cardiac membrane protease corin. J. Biol. Chem. 2011 (in press).