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|Title:||Serine carboxypeptidase SCPEP1 and cathepsin a play complementary roles in regulation of vasoconstriction via inactivation of endothelin-1||Authors:||Pan, Xuefang
Lavoie, Julie L.
Pshezhetsky, Alexey V.
|Issue Date:||Feb-2014||Publisher:||Public Library of Science||Source:||Pan, X., Grigoryeva, L., Seyrantepe, V., Peng, J., Kollmann, K., Tremblay, J., Lavoie, J. L., Hinek, A., Lübke, T., and Pshezhetsky, A. V. (2014). Serine Carboxypeptidase SCPEP1 and Cathepsin A Play Complementary Roles in Regulation of Vasoconstriction via Inactivation of Endothelin-1. PLoS Genetics, 10(2). doi:10.1371/journal.pgen.1004146||Abstract:||The potent vasoconstrictor peptides, endothelin 1 (ET-1) and angiotensin II control adaptation of blood vessels to fluctuations of blood pressure. Previously we have shown that the circulating level of ET-1 is regulated through its proteolytic cleavage by secreted serine carboxypeptidase, cathepsin A (CathA). However, genetically-modified mouse expressing catalytically inactive CathA S190A mutant retained about 10-15% of the carboxypeptidase activity against ET-1 in its tissues suggesting a presence of parallel/redundant catabolic pathway(s). In the current work we provide direct evidence that the enzyme, which complements CathA action towards ET-1 is a retinoid-inducible lysosomal serine carboxypeptidase 1 (Scpep1), a CathA homolog with previously unknown biological function. We generated a mouse strain devoid of both CathA and Scpep1 activities (DD mice) and found that in response to high-salt diet and systemic injections of ET-1 these animals showed significantly increased blood pressure as compared to wild type mice or those with single deficiencies of CathA or Scpep1. We also found that the reactivity of mesenteric arteries from DD mice towards ET-1 was significantly higher than that for all other groups of mice. The DD mice had a reduced degradation rate of ET-1 in the blood whereas their cultured arterial vascular smooth muscle cells showed increased ET-1-dependent phosphorylation of myosin light chain 2. Together, our results define the biological role of mammalian serine carboxypeptidase Scpep1 and suggest that Scpep1 and CathA together participate in the control of ET-1 regulation of vascular tone and hemodynamics.||URI:||http://doi.org/10.1371/journal.pgen.1004146
|Appears in Collections:||Molecular Biology and Genetics / Moleküler Biyoloji ve Genetik|
PubMed İndeksli Yayınlar Koleksiyonu / PubMed Indexed Publications Collection
Scopus İndeksli Yayınlar Koleksiyonu / Scopus Indexed Publications Collection
WoS İndeksli Yayınlar Koleksiyonu / WoS Indexed Publications Collection
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