Role of homocysteinylation of ACE in endothelial dysfunction of arteries

16Citations
Citations of this article
12Readers
Mendeley users who have this article in their library.

This article is free to access.

Abstract

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.

Cite

CITATION STYLE

APA

Huang, A., Pinto, J. T., Froogh, G., Kandhi, S., Qin, J., Wolin, M. S., … Sun, D. (2015). Role of homocysteinylation of ACE in endothelial dysfunction of arteries. American Journal of Physiology - Heart and Circulatory Physiology, 308(1), H92–H100. https://doi.org/10.1152/ajpheart.00577.2014

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free