1. Lysozyme and bilirubin bind to ACE and regulate its conformation and shedding.
- Author
-
Danilov SM, Lünsdorf H, Akinbi HT, Nesterovitch AB, Epshtein Y, Letsiou E, Kryukova OV, Piegeler T, Golukhova EZ, Schwartz DE, Dull RO, Minshall RD, Kost OA, and Garcia JG
- Subjects
- Animals, Antibodies, Monoclonal chemistry, CHO Cells, Case-Control Studies, Cell Membrane metabolism, Cricetinae, Cricetulus, Flow Cytometry, Humans, Intercellular Signaling Peptides and Proteins, Mice, Mutation, Peptides chemistry, Phenotype, Protein Binding, Protein Domains, Pulmonary Surfactant-Associated Protein C, Sarcoidosis blood, Surface Plasmon Resonance, Bilirubin chemistry, Muramidase chemistry, Peptidyl-Dipeptidase A chemistry
- 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.
- Published
- 2016
- Full Text
- View/download PDF