Lysozyme and bilirubin bind to ACE and regulate its conformation and shedding

Sergei M. Danilov, Heinrich Lünsdorf, Henry T. Akinbi, Andrew B. Nesterovitch, Yuliya Epshtein, Eleftheria Letsiou, Olga V. Kryukova, Tobias Piegeler, Elena Z. Golukhova, David E. Schwartz, Randal O. Dull, Richard D. Minshall, Olga A. Kost, Joe G N Garcia

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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.

Original languageEnglish (US)
Article number34913
JournalScientific Reports
Volume6
DOIs
StatePublished - Oct 13 2016

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Danilov, S. M., Lünsdorf, H., Akinbi, H. T., Nesterovitch, A. B., Epshtein, Y., Letsiou, E., Kryukova, O. V., Piegeler, T., Golukhova, E. Z., Schwartz, D. E., Dull, R. O., Minshall, R. D., Kost, O. A., & Garcia, J. G. N. (2016). Lysozyme and bilirubin bind to ACE and regulate its conformation and shedding. Scientific Reports, 6, [34913]. https://doi.org/10.1038/srep34913