Role of homocysteinylation of ACE in endothelial dysfunction of arteries
| Autor: | Michael S. Wolin, Jun Qin, Sharath Kandhi, Ghezal Froogh, Dong Sun, John T. Pinto, Thomas H. Hintze, An Huang |
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| Rok vydání: | 2015 |
| Předmět: |
Male
medicine.medical_specialty Homocysteine Endothelium Physiology Vascular Biology and Microcirculation Myocytes Smooth Muscle Angiotensin-Converting Enzyme Inhibitors Peptidyl-Dipeptidase A Nitric Oxide Nitric oxide chemistry.chemical_compound Methionine Superoxides Physiology (medical) Internal medicine medicine Animals Rats Wistar Endothelial dysfunction Mesenteric arteries NADPH oxidase biology NADPH Oxidases Angiotensin-converting enzyme medicine.disease Coronary Vessels Angiotensin II Mesenteric Arteries Rats Vasodilation Endocrinology medicine.anatomical_structure chemistry biology.protein Endothelium Vascular Cardiology and Cardiovascular Medicine Angiotensin II Type 1 Receptor Blockers |
| Zdroj: | American Journal of Physiology-Heart and Circulatory Physiology. 308:H92-H100 |
| ISSN: | 1522-1539 0363-6135 |
| Popis: | The direct impact of de novo synthesis of homocysteine (Hcy) and its reactive metabolites, Hcy-S-S-Hcy and Hcy thiolactone (HCTL), on vascular function has not been fully elucidated. We hypothesized that Hcy synthesized within endothelial cells affects activity of angiotensin-converting enzyme (ACE) by direct homocysteinylation of its amino- and/or sulfhydryl moieties. This covalent modification enhances ACE reactivity toward angiotensin II (ANG II)-NADPH oxidase-superoxide-dependent endothelial dysfunction. Mesenteric and coronary arteries isolated from normal rats were incubated for 3 days with or without exogenous methionine (Met, 0.1–0.3 mM), a precursor to Hcy. Incubation of arteries in Met-free media resulted in time-dependent decreases in vascular Hcy formation. By contrast, vessels incubated with Met produced Hcy in a dose-dependent manner. There was a notably greater de novo synthesis of Hcy from endothelial than from smooth muscle cells. Enhanced levels of Hcy production significantly impaired shear stress-induced dilation and release of nitric oxide, events that are associated with elevated production of vascular superoxide. Each of these processes was attenuated by ANG II type I receptor blocker or ACE and NADPH oxidase inhibitors. In addition, in vitro exposure of purified ACE to Hcy-S-S-Hcy/HCTL resulted in formation of homocysteinylated ACE and an enhanced ACE activity. The enhanced ACE activity was confirmed in isolated coronary and mesenteric arteries that had been exposed directly to Hcy-S-S-Hcy/HCTL or after Met incubation. In conclusion, vasculature-derived Hcy initiates endothelial dysfunction that, in part, may be mediated by ANG II-dependent activation of NADPH oxidase in association with homocysteinylation of ACE. |
| Databáze: | OpenAIRE |
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