Putative Nox2 inhibitors worsen homocysteine-induced impaired acetylcholine-mediated relaxation

SMITH, Renee M., Sudarshan RAI, Peter KRUŽLIAK, Alan HAYES and Anthony ZULLI. Putative Nox2 inhibitors worsen homocysteine-induced impaired acetylcholine-mediated relaxation. NUTRITION METABOLISM AND CARDIOVASCULAR DISEASES. OXFORD: ELSEVIER SCI LTD, 2019, vol. 29, No 8, p. 856-864. ISSN 0939-4753. Available from: https://dx.doi.org/10.1016/j.numecd.2019.05.051.

Basic information

Original name

Putative Nox2 inhibitors worsen homocysteine-induced impaired acetylcholine-mediated relaxation

Authors

SMITH, Renee M. (36 Australia, guarantor), Sudarshan RAI (36 Australia), Peter KRUŽLIAK (703 Slovakia, belonging to the institution), Alan HAYES (36 Australia) and Anthony ZULLI (36 Australia)

Edition

NUTRITION METABOLISM AND CARDIOVASCULAR DISEASES, OXFORD, ELSEVIER SCI LTD, 2019, 0939-4753

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Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30201 Cardiac and Cardiovascular systems

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 3.700

RIV identification code

RIV/00216224:14110/19:00111782

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1016/j.numecd.2019.05.051

UT WoS

000476511900012

Keywords in English

Acetylcholine; Acetylcholine-mediated vasorelaxation; Homocysteine; Nox2; Pharmacology

Tags

14110121, rivok

Tags

International impact, Reviewed

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Abstract

V originále

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.