title: Serine carboxypeptidase SCPEP1 and Cathepsin A play complementary roles in regulation of vasoconstriction via inactivation of endothelin-1.
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.
authors.affiliation: Department of Medical Genetics, CHU Sainte-Justine Research Center, University of Montreal, Montreal, Canada.
authors.forename: Xuefang
authors.initials: X
authors.lastname: Pan
authors.affiliation: Department of Medical Genetics, CHU Sainte-Justine Research Center, University of Montreal, Montreal, Canada.
authors.forename: Lubov
authors.initials: L
authors.lastname: Grigoryeva
authors.affiliation: Izmir Institute of Technology, Department of Molecular Biology and Genetics, Urla Izmir, Turkey.
authors.forename: Volkan
authors.initials: V
authors.lastname: Seyrantepe
authors.affiliation: CHUM Research Center and the Department of Kinesiology, University of Montreal, Montreal, Canada.
authors.forename: Junzheng
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Biochemistry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Kollmann
authors.affiliation: CHUM Research Center and the Department of Kinesiology, University of Montreal, Montreal, Canada.
authors.forename: Johanne
authors.initials: J
authors.lastname: Tremblay
authors.affiliation: CHUM Research Center and the Department of Kinesiology, University of Montreal, Montreal, Canada.
authors.forename: Julie L
authors.initials: JL
authors.lastname: Lavoie
authors.affiliation: Cardiovascular Research Program, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
authors.forename: Aleksander
authors.initials: A
authors.lastname: Hinek
authors.affiliation: Department of Chemistry, Biochemistry I, Bielefeld University, Bielefeld, Germany.
authors.forename: Torben
authors.initials: T
authors.lastname: Lübke
authors.affiliation: Department of Medical Genetics, CHU Sainte-Justine Research Center, University of Montreal, Montreal, Canada ; Department of Anatomy and Cell Biology, McGill University, Montreal, Canada.
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Pshezhetsky
mesh_terms: D000804:Angiotensin II / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000235:genetics; D002268:Carboxypeptidases / Q000235:genetics / Q000378:metabolism*; D043402:Cathepsin A / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D006439:Hemodynamics / Q000235:genetics; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000473:pathology; D051379:Mice; D014661:Vasoconstriction / Q000235:genetics
chemical_list: D019332:Endothelin-1; D000804:Angiotensin II; D002268:Carboxypeptidases; C436327:SCPEP1 protein, human; D043402:Cathepsin A