title: Mice, double deficient in lysosomal serine carboxypeptidases Scpep1 and Cathepsin A develop the hyperproliferative vesicular corneal dystrophy and hypertrophic skin thickenings.
abstract: Vasoactive and mitogenic peptide, endothelin-1 (ET-1) plays an important role in physiology of the ocular tissues by regulating the growth of corneal epithelial cells and maintaining the hemodynamics of intraocular fluids. We have previously established that ET-1 can be degraded in vivo by two lysosomal/secreted serine carboxypeptidases, Cathepsin A (CathA) and Serine Carboxypeptidase 1 (Scpep1) and that gene-targeted CathAS190A /Scpep1-/- mice, deficient in CathA and Scpep1 have a prolonged half-life of circulating ET-1 associated with systemic hypertension. In the current work we report that starting from 6 months of age, ~43% of CathAS190A /Scpep1-/- mice developed corneal clouding that eventually caused vision impairment. Histological evaluation of these mice demonstrated a selective fibrotic thickening and vacuolization of the corneas, resembling human hyperproliferative vesicular corneal stromal dystrophy and coexisting with a peculiar thickening of the skin epidermis. Moreover, we found that cultured corneal epithelial cells, skin fibroblasts and vascular smooth muscle cells derived from CathA/Scpep1-deficient mice, demonstrated a significantly higher proliferative response to treatment with exogenous ET-1, as compared with cells from wild type mice. We also detected increased activation level of ERK1/2 and AKT kinases involved in cell proliferation in the ET-1-treated cultured cells from CathA/Scpep1 deficient mice. Together, results from our experimental model suggest that; in normal tissues the tandem of serine carboxypeptidases, Scpep1 and CathA likely constitutes an important part of the physiological mechanism responsible for the balanced elimination of heightened levels of ET-1 that otherwise would accumulate in tissues and consequently contribute to development of the hyper-proliferative corneal dystrophy and abnormal skin thickening.
authors.affiliation: Department of Medical Genetics, CHU Sainte-Justine Research Center, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Xuefang
authors.initials: X
authors.lastname: Pan
authors.affiliation: Cardiovascular Research Program, the Hospital for Sick Children and Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada.
authors.forename: Yanting
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Biochemistry I, Bielefeld University, Bielefeld, Germany.
authors.forename: Torben
authors.initials: T
authors.lastname: Lübke
authors.affiliation: Cardiovascular Research Program, the Hospital for Sick Children and Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada.
authors.forename: Aleksander
authors.initials: A
authors.lastname: Hinek
authors.affiliation: Department of Medical Genetics, CHU Sainte-Justine Research Center, University of Montreal, Montreal, Quebec, Canada.|Department of Anatomy and Cell Biology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Alexey V
authors.identifier: http://orcid.org/0000-0002-6612-1062
authors.initials: AV
authors.lastname: Pshezhetsky
mesh_terms: D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism; D002268:Carboxypeptidases / Q000235:genetics* / Q000378:metabolism; D043402:Cathepsin A / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D003317:Corneal Dystrophies, Hereditary / Q000235:genetics* / Q000378:metabolism; D019332:Endothelin-1 / Q000494:pharmacology; D004817:Epidermis / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D005355:Fibrosis; D006439:Hemodynamics; D008247:Lysosomes / Q000201:enzymology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D058628:Myofibroblasts / Q000166:cytology; D010766:Phosphorylation; D012867:Skin / Q000473:pathology*
chemical_list: D019332:Endothelin-1; D002268:Carboxypeptidases; C486671:Scpep1 protein, mouse; D043402:Cathepsin A