Genetic Deletion of NADPH Oxidase 1 Rescues Microvascular Function in Mice with Metabolic Disease
Rationale: Early vascular changes in metabolic disease that precipitate the development of cardiovascular complications are largely driven by reactive oxygen species (ROS) accumulation, yet the extent to which excess ROS derive from specific Nox isoforms remains ill-defined.
Objective: Identify the role of Nox1 in the development of microvascular dysfunction in metabolic disease.
Methods and Results: Four genotypes were generated by breeding Nox1 knock-out (KO) mice with db/db mice: lean (HdbWnox1); lean Nox1 KO (HdbKnox1); obese (KdbWnox1); obese KK (KdbKnox1). The degree of adiposity, insulin resistance, and dyslipidemia in KW mice were not influenced by Nox1 deletion as determined by NMR spectroscopy, glucose tolerance tests, and plasma analyses. Endothelium-dependent responses to acetylcholine (Ach) in pressurized mesenteric arteries were reduced in KW vs. HW (p < 0.01), while deletion of Nox1 in KW mice normalized dilation. Vasodilator responses following inhibition of nitric oxide (NO) synthase blunted Ach responses in KK and lean controls, but had no impact in KW, attributing recovered dilatory capacity in KK to normalization of NO. Ach responses were improved (p < 0.05) with Tempol, and histochemistry revealed oxidative stress in KW animals, while Tempol had no impact and ROS staining was negligible in KK. Blunted dilatory responses to a NO donor and loss of myogenic tone in KW animals were also rescued with Nox1 deletion.
Conclusions: Nox1 deletion reduces oxidant load and restores microvascular health in db/db mice without influencing the degree of metabolic dysfunction. Therefore, targeted Nox1 inhibition may be effective in the prevention of vascular complications.
- Received September 14, 2016.
- Revision received June 19, 2017.
- Accepted July 5, 2017.
Circulation Research is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDervis License (http://creativecommons.org/licenses/by-nc-nd/3.0/), which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.