title: Enzymatic activity of lysosomal carboxypeptidase (cathepsin) A is required for proper elastic fiber formation and inactivation of endothelin-1.
abstract: BACKGROUND
  Lysosomal carboxypeptidase, cathepsin A (protective protein, CathA), is a component of the lysosomal multienzyme complex along with beta-galactosidase (GAL) and sialidase Neu1, where it activates Neu1 and protects GAL and Neu1 against the rapid proteolytic degradation. On the cell surface, CathA, Neu1, and the enzymatically inactive splice variant of GAL form the elastin-binding protein complex. In humans, genetic defects of CathA cause galactosialidosis, a metabolic disease characterized by combined deficiency of CathA, GAL, and Neu1 and a lysosomal storage of sialylated glycoconjugates. However, several phenotypic features of galactosialidosis patients, including hypertension and cardiomyopathies, cannot be explained by the lysosomal storage. These observations suggest that CathA may be involved in hemodynamic functions that go beyond its protective activity in the lysosome.
  
  
  RESULTS
  We generated a gene-targeted mouse in which the active CathA was replaced with a mutant enzyme carrying a Ser190Ala substitution in the active site. These animals expressed physiological amounts of catalytically inactive CathA protein, capable of forming lysosomal multienzyme complex, and did not develop secondary deficiency of Neu1 and GAL. Conversely, the mice showed a reduced degradation rate of the vasoconstrictor peptide, endothelin-1, and significantly increased arterial blood pressure. CathA-deficient mice also displayed scarcity of elastic fibers in lungs, aortic adventitia, and skin.
  
  
  CONCLUSIONS
  Our results provide the first evidence that CathA acts in vivo as an endothelin-1-inactivating enzyme and strongly confirm a crucial role of this enzyme in effective elastic fiber formation.
authors.affiliation: Department of Medical Genetics, CHU Sainte Justine Research Center, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Volkan
authors.initials: V
authors.lastname: Seyrantepe
authors.forename: Aleksander
authors.initials: A
authors.lastname: Hinek
authors.forename: Junzheng
authors.initials: J
authors.lastname: Peng
authors.forename: Michael
authors.initials: M
authors.lastname: Fedjaev
authors.forename: Sheila
authors.initials: S
authors.lastname: Ernest
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Kadota
authors.forename: Maryssa
authors.initials: M
authors.lastname: Canuel
authors.forename: Kohji
authors.initials: K
authors.lastname: Itoh
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Morales
authors.forename: Julie
authors.initials: J
authors.lastname: Lavoie
authors.forename: Johanne
authors.initials: J
authors.lastname: Tremblay
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Pshezhetsky
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D043402:Cathepsin A / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured / Q000201:enzymology / Q000648:ultrastructure; D004547:Elastic Tissue / Q000378:metabolism* / Q000648:ultrastructure; D004549:Elastin / Q000378:metabolism; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000502:physiology; D004789:Enzyme Activation; D005347:Fibroblasts / Q000201:enzymology / Q000648:ultrastructure; D005813:Genes, Synthetic; D006973:Hypertension / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008247:Lysosomes / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009097:Multienzyme Complexes; D009439:Neuraminidase / Q000378:metabolism; D009474:Neurons / Q000201:enzymology / Q000648:ultrastructure; D009928:Organ Specificity; D012333:RNA, Messenger / Q000096:biosynthesis; D017673:Sodium Chloride, Dietary / Q000009:adverse effects; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D009097:Multienzyme Complexes; D012333:RNA, Messenger; D017673:Sodium Chloride, Dietary; D004549:Elastin; C110128:Neu1 protein, mouse; D009439:Neuraminidase; D001616:beta-Galactosidase; D043402:Cathepsin A