Origin of serpin-mediated regulation of coagulation and blood pressure

Wang Y, Köster K, Lummer M, Ragg H (2014)
PLoS ONE 9(5).

Journal Article | Published | English
Vertebrates evolved an endothelium-lined hemostatic system and a pump-driven pressurized circulation with a finely-balanced coagulation cascade and elaborate blood pressure control over the past 500 million years. Genome analyses have identified principal components of the ancestral coagulation system, however, how this complex trait was originally regulated is largely unknown. Likewise, little is known about the roots of blood pressure control in vertebrates. Here we studied three members of the serpin superfamily that interfere with procoagulant activity and blood pressure of lampreys, a group of basal vertebrates. Angiotensinogen from these jawless fish was found to fulfill a dual role by operating as a highly selective thrombin inhibitor that is activated by heparin-related glycosaminoglycans, and concurrently by serving as source of effector peptides that activate type 1 angiotensin receptors. Lampreys, uniquely among vertebrates, thus use angiotensinogen for interference with both coagulation and osmo- and pressure regulation. Heparin cofactor II from lampreys, in contrast to its paralogue angiotensinogen, is preferentially activated by dermatan sulfate, suggesting that these two serpins affect different facets of thrombin’s multiple roles. Lampreys also express a lineage-specific serpin with anti-factor Xa activity, which demonstrates that another important procoagulant enzyme is under inhibitory control. Comparative genomics suggests that orthologues of these three serpins were key components of the ancestral hemostatic system. It appears that, early in vertebrate evolution, coagulation and osmo- and pressure regulation crosstalked through antiproteolytically active angiotensinogen, a feature that was lost during vertebrate radiation, though in gnathostomes interplay between these traits is effective.
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Article Processing Charge funded by the Deutsche Forschungsgemeinschaft and the Open Access Publication Fund of Bielefeld University.

Cite this

Wang Y, Köster K, Lummer M, Ragg H. Origin of serpin-mediated regulation of coagulation and blood pressure. PLoS ONE. 2014;9(5).
Wang, Y., Köster, K., Lummer, M., & Ragg, H. (2014). Origin of serpin-mediated regulation of coagulation and blood pressure. PLoS ONE, 9(5).
Wang, Y., Köster, K., Lummer, M., and Ragg, H. (2014). Origin of serpin-mediated regulation of coagulation and blood pressure. PLoS ONE 9.
Wang, Y., et al., 2014. Origin of serpin-mediated regulation of coagulation and blood pressure. PLoS ONE, 9(5).
Y. Wang, et al., “Origin of serpin-mediated regulation of coagulation and blood pressure”, PLoS ONE, vol. 9, 2014.
Wang, Y., Köster, K., Lummer, M., Ragg, H.: Origin of serpin-mediated regulation of coagulation and blood pressure. PLoS ONE. 9, (2014).
Wang, Yunjie, Köster, Katharina, Lummer, Martina, and Ragg, Hermann. “Origin of serpin-mediated regulation of coagulation and blood pressure”. PLoS ONE 9.5 (2014).
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45 References

Data provided by Europe PubMed Central.

MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods.
Tamura K, Peterson D, Peterson N, Stecher G, Nei M, Kumar S., Mol. Biol. Evol. 28(10), 2011
PMID: 21546353
Molecular determinants of angiotensin II type 1 receptor functional selectivity.
Aplin M, Bonde MM, Hansen JL., J. Mol. Cell. Cardiol. 46(1), 2009
PMID: 18848837
Role of Phe308 in the seventh transmembrane domain of the AT2 receptor in ligand binding and signaling.
Pulakat L, Mandavia CH, Gavini N., Biochem. Biophys. Res. Commun. 319(4), 2004
PMID: 15194486
Evolution by gene duplication: an update
Vertebrate serpins: construction of a conflict-free phylogeny by combining exon-intron and diagnostic site analyses.
Ragg H, Lokot T, Kamp PB, Atchley WR, Dress A., Mol. Biol. Evol. 18(4), 2001
PMID: 11264410
Thrombin inhibition by the serpins.
Huntington JA., J. Thromb. Haemost. 11 Suppl 1(), 2013
PMID: 23809129
Genomic evidence for a simpler clotting scheme in jawless vertebrates.
Doolittle RF, Jiang Y, Nand J., J. Mol. Evol. 66(2), 2008
PMID: 18283387
Semin Thromb Hemostas
Differential PI 3-kinase dependence of early and late phases of recycling of the internalized AT1 angiotensin receptor.
Hunyady L, Baukal AJ, Gaborik Z, Olivares-Reyes JA, Bor M, Szaszak M, Lodge R, Catt KJ, Balla T., J. Cell Biol. 157(7), 2002
PMID: 12070129
Angiotensin II revisited: new roles in inflammation, immunology and aging.
Benigni A, Cassis P, Remuzzi G., EMBO Mol Med 2(7), 2010
PMID: 20597104
The angiotensin system elements in invertebrates.
Salzet M, Deloffre L, Breton C, Vieau D, Schoofs L., Brain Res. Brain Res. Rev. 36(1), 2001
PMID: 11516771
Screening mammal biodiversity using DNA from leeches.
Schnell IB, Thomsen PF, Wilkinson N, Rasmussen M, Jensen LR, Willerslev E, Bertelsen MF, Gilbert MT., Curr. Biol. 22(8), 2012
PMID: 22537625
Thrombin as a multi-functional enzyme. Focus on in vitro and in vivo effects.
Siller-Matula JM, Schwameis M, Blann A, Mannhalter C, Jilma B., Thromb. Haemost. 106(6), 2011
PMID: 21979864
The roles of proteinase-activated receptors in the vascular physiology and pathophysiology.
Hirano K., Arterioscler. Thromb. Vasc. Biol. 27(1), 2007
PMID: 17095716
Is thrombin a key player in the 'coagulation-atherogenesis' maze?
Borissoff JI, Spronk HM, Heeneman S, ten Cate H., Cardiovasc. Res. 82(3), 2009
PMID: 19228706
Heparin cofactor II, a serine protease inhibitor, promotes angiogenesis via activation of the AMP-activated protein kinase-endothelial nitric-oxide synthase signaling pathway.
Ikeda Y, Aihara K, Yoshida S, Iwase T, Tajima S, Izawa-Ishizawa Y, Kihira Y, Ishizawa K, Tomita S, Tsuchiya K, Sata M, Akaike M, Kato S, Matsumoto T, Tamaki T., J. Biol. Chem. 287(41), 2012
PMID: 22904320


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