title: Lysozyme and bilirubin bind to ACE and regulate its conformation and shedding.
abstract: Angiotensin I-converting enzyme (ACE) hydrolyzes numerous peptides and is a critical participant in blood pressure regulation and vascular remodeling. Elevated tissue ACE levels are associated with increased risk for cardiovascular and respiratory disorders. Blood ACE concentrations are determined by proteolytic cleavage of ACE from the endothelial cell surface, a process that remains incompletely understood. In this study, we identified a novel ACE gene mutation (Arg532Trp substitution in the N domain of somatic ACE) that increases blood ACE activity 7-fold and interrogated the mechanism by which this mutation significantly increases blood ACE levels. We hypothesized that this ACE mutation disrupts the binding site for blood components which may stabilize ACE conformation and diminish ACE shedding. We identified the ACE-binding protein in the blood as lysozyme and also a Low Molecular Weight (LMW) ACE effector, bilirubin, which act in concert to regulate ACE conformation and thereby influence ACE shedding. These results provide mechanistic insight into the elevated blood level of ACE observed in patients on ACE inhibitor therapy and elevated blood lysozyme and ACE levels in sarcoidosis patients.
authors.affiliation: Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL, USA.|Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Sergei M
authors.initials: SM
authors.lastname: Danilov
authors.affiliation: Central Facility of Microscopy, Helmholtz-Center of Infection Research, Braunschweig, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Lünsdorf
authors.affiliation: Divisions of Pulmonary Biology and Neonatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Henry T
authors.initials: HT
authors.lastname: Akinbi
authors.affiliation: Department of Dermatology, Rush University, Chicago, IL, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Nesterovitch
authors.affiliation: Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Epshtein
authors.affiliation: Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Letsiou
authors.affiliation: Faculty of Chemistry, Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Olga V
authors.initials: OV
authors.lastname: Kryukova
authors.affiliation: Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL, USA.|Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Tobias
authors.initials: T
authors.lastname: Piegeler
authors.affiliation: Bakulev Center for Cardiovascular Surgery, Moscow, Russia.
authors.forename: Elena Z
authors.initials: EZ
authors.lastname: Golukhova
authors.affiliation: Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Schwartz
authors.affiliation: Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Randal O
authors.initials: RO
authors.lastname: Dull
authors.affiliation: Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL, USA.|Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Minshall
authors.affiliation: Faculty of Chemistry, Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Kost
authors.affiliation: Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL, USA.|University of Arizona Health Sciences, Tucson, AZ, USA.
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D001663:Bilirubin / Q000737:chemistry*; D016466:CHO Cells; D016022:Case-Control Studies; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D005434:Flow Cytometry; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D009113:Muramidase / Q000737:chemistry*; D009154:Mutation; D010455:Peptides / Q000737:chemistry; D007703:Peptidyl-Dipeptidase A / Q000737:chemistry*; D010641:Phenotype; D011485:Protein Binding; D000072417:Protein Domains; D037721:Pulmonary Surfactant-Associated Protein C; D012507:Sarcoidosis / Q000097:blood; D020349:Surface Plasmon Resonance
chemical_list: D000911:Antibodies, Monoclonal; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D037721:Pulmonary Surfactant-Associated Protein C; C489680:Sftpc protein, mouse; D009113:Muramidase; C488034:ACE protein, human; D007703:Peptidyl-Dipeptidase A; D001663:Bilirubin