Publication details
Putative Nox2 inhibitors worsen homocysteine-induced impaired acetylcholine-mediated relaxation
| Authors | |
|---|---|
| Year of publication | 2019 |
| Type | Article in Periodical |
| Magazine / Source | NUTRITION METABOLISM AND CARDIOVASCULAR DISEASES |
| MU Faculty or unit | |
| Citation | |
| Web | http://dx.doi.org/10.1016/j.numecd.2019.05.051 |
| Doi | http://dx.doi.org/10.1016/j.numecd.2019.05.051 |
| Keywords | Acetylcholine; Acetylcholine-mediated vasorelaxation; Homocysteine; Nox2; Pharmacology |
| Description | Background and aim: Increased homocysteine (Hcy) is associated with coronary artery disease (CAD). Hcy increases reactive oxygen species (ROS) via NADPH oxidases (Nox), reducing acetylcholine-mediated vasorelaxation. We aimed to determine if putative Nox2 inhibitors prevent Hcy-impaired acetylcholine-mediated vasorelaxation. Methods and results: New Zealand White rabbit and wild-type (C57BL/6) and Nox2(-/-) (NOX) mice aortic rings were mounted in organ baths. Rabbit rings were incubated with either apocynin (10 mu M), gp91ds-tat (GP, 1 mu M) or PhoxI2 (1 mu M) and mice rings GP (1 mu M) only. Some rabbit rings were incubated with 3 mM Hcy, before pre-contraction, followed by dose-response relaxation to acetylcholine (ACh; 0.01 mu M-10 mu M). In rabbit rings treated with Hcy and GP, O-2(-) donor pyrogallol (1 mu M) or Akt activator SC79 (1 mu M) was added 5 min before ACh. Mice rings were used to compare Nox2 deletion to normal acetylcholine-mediated relaxation. In rabbits, Hcy reduced acetylcholine-mediated relaxation vs. control (p < 0.0001). Treatment + Hcy reduced relaxation compared with treatment alone (p < 0.0001). Pyrogallol and SC79 reversed the response of GP + Hcy (p = 0.0001). In mice, Nox2 deletion reduced acetylcholine-mediated vasorelaxation. Rabbit tissue analysis revealed that Hcy reduced eNOS phosphorylation at Thr(495) and increased eNOS phosphorylation at Ser(1177); no further alteration at Thr(495) was observed with GP. In contrast, GP prevented increased phosphorylation at Ser(1177). Conclusions: Apocynin, GP and PhoxI2 worsens acetylcholine-mediated vascular relaxation in rabbit aorta, which is supported by results from mouse Nox2 deletion data. These inhibitors worsen Hcy-induced vascular dysfunction, suggesting that current putative Nox2 inhibitors might not be useful in treating HHcy. (C) 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved. |