Role of homocysteinylation of ACE in endothelial dysfunction of arteries

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.

Elevated Homocysteine Concentrations Decrease the Antihypertensive Effect of Angiotensin-Converting Enzyme Inhibitors in Hypertensive Patients

“…Our study served to bridge previous laboratory findings [11][12][13][14] with real-world clinical translation. It is the first to demonstrate a positive association between Hcy concentration and SBP or DBP levels at baseline and to elucidate that higher baseline Hcy concentrations, even that of a moderate increase (10-15 μmol/L), are significantly associated with decreased antihypertensive response to short-or long-term enalapril-based antihypertensive treatments in previously untreated hypertensive patients.…”

“…2 Therefore, it is possible that during HHcy, reduced H 2 S promotes ACE activity that may lead to the upregulation of angiotensin II. Another study 13 suggested that increased production of endothelial Hcy and its reactive metabolites (Hcy-S-S-Hcy/Hcy-thiolactone) produces N-and S-homocysteinylation of ACE to increase its activity, resulting in the upregulation of the angiotensin II. The exact mechanism by which elevated Hcy reduces enalapril efficacy still needs to be investigated thoroughly before a conclusion can be drawn.…”

“…23 Third, previous animal studies found that long-term treatment from ACEI or angiotensin receptor blocker treatment could mitigate pathological vascular damage induced by HHcy. 13,24 Therefore, the long-term use of ACEIs may also possibly attenuate the adverse effect of elevated Hcy concentrations and the beneficial effect of Hcy lowering on BP reduction. Overall, the association between Hcy reduction folic acid therapy and the adverse effect of elevated Hcy on the antihypertensive efficacy of enalapril still needs to be further investigated in future studies.…”

“…[11][12][13] Moreover, higher Hcy concentrations have been shown to significantly reduce bradykinin-induced changes in BP, blood flow, and vascular resistance. 14 The main mechanisms of action of ACE inhibitors (ACEIs) include decreased formation of the vasoconstrictor angiotensin II and increased levels of the vasodilator bradykinin.…”

Functional and Biochemical Endothelial Profiling In Vivo in a Murine Model of Endothelial Dysfunction; Comparison of Effects of 1-Methylnicotinamide and Angiotensin-converting Enzyme Inhibitor

“…These results seem consistent with our observations showing the reduction in plasma ADMA concentration as well as Hcy concentration that was linked to an improved endothelium-dependent vascular relaxation after MNA. Interestingly, Huang et al (2015) showed that Hcy synthesized in endothelium (after Met administration) affected activity of ACE by direct homocysteinylation of its amino- and/or sulfhydryl- moieties. This modification enhanced ACE reactivity toward Ang II and consequently led to NADPH oxidase-superoxide-dependent endothelial dysfunction.…”