Lysozyme and bilirubin bind to ACE and regulate its conformation and shedding.
Lysozyme and bilirubin bind to ACE and regulate its conformation and shedding.
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DOI：
10.1038/srep34913
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发表时间：
2016-10-13
影响因子：
4.6
通讯作者：
Garcia JG
中科院分区：
文献类型：
--
作者：
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;Garcia JG
血管紧张素i转换酶（ACE）水解多种肽，是血压调节和血管重塑的关键参与者。组织ACE水平升高与心血管和呼吸系统疾病的风险增加有关。血液中ACE浓度是由内皮细胞表面的ACE蛋白水解裂解决定的，这一过程尚不完全清楚。在这项研究中，我们发现了一个新的ACE基因突变（Arg532Trp替换在体细胞ACE的N结构域），使血液ACE活性增加了7倍，并询问了该突变显著提高血液ACE水平的机制。我们假设这种ACE突变破坏了血液成分的结合位点，从而稳定ACE构象并减少ACE脱落。我们发现血液中的ACE结合蛋白为溶菌酶和低分子量（LMW） ACE效应物胆红素，它们共同调节ACE构象，从而影响ACE脱落。这些结果为ACE抑制剂治疗患者血中ACE水平升高以及结节病患者血中溶菌酶和ACE水平升高提供了机制见解。
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.
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影响因子：
3.7
作者：
Clarke NE;Fisher MJ;Porter KE;Lambert DW;Turner AJ
通讯作者：
Turner AJ
影响因子：
4.4
作者：
Balyasnikova, Irina V.;Skirgello, Olga E.;Danilov, Sergei M.
通讯作者：
Danilov, Sergei M.
影响因子：
4.4
作者：
Dufour, C;Casane, D;Jeunemaitre, X
通讯作者：
Jeunemaitre, X
影响因子：
4.1
作者：
Balyasnikova, IV;Karran, EH;Danilov, SM
通讯作者：
Danilov, SM
影响因子：
2.6
作者：
Danilov, SM;Sadovnikova, E;Adema, GJ
通讯作者：
Adema, GJ