Genetic deletion of NADPH oxidase 1 rescues microvascular function in mice with metabolic disease

Jennifer A. Thompson, Sebastian Larion, James D. Mintz, Eric Jacques Belin de Chantemele, David J Fulton, David W Stepp

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Rationale: Early vascular changes in metabolic disease that precipitate the development of cardiovascular complications are largely driven by reactive oxygen species accumulation, yet the extent to which excess reactive oxygen species derive from specific NADPH oxidase 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 knockout mice with db/db mice: lean (HdbWnox1), lean Nox1 knockout (HdbKnox1), obese (KdbWnox1), and obese KK (KdbKnox1). The degree of adiposity, insulin resistance, and dyslipidemia in KW mice was not influenced by Nox1 deletion as determined by nuclear magnetic resonance spectroscopy, glucose tolerance tests, and plasma analyses. Endothelium-dependent responses to acetylcholine in pressurized mesenteric arteries were reduced in KW versus HW (P<0.01), whereas deletion of Nox1 in KW mice normalized dilation. Vasodilator responses after inhibition of NO synthase blunted acetylcholine responses in KK and lean controls, but had no impact in KW, attributing recovered dilatory capacity in KK to normalization of NO. Acetylcholine responses were improved (P<0.05) with Tempol, and histochemistry revealed oxidative stress in KW animals, whereas Tempol had no impact and reactive oxygen species staining was negligible in KK. Blunted dilatory responses to an 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.

Original languageEnglish (US)
Pages (from-to)502-511
Number of pages10
JournalCirculation research
Volume121
Issue number5
DOIs
StatePublished - Aug 1 2017

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Metabolic Diseases
Acetylcholine
Reactive Oxygen Species
Blood Vessels
Mesenteric Arteries
NADPH Oxidase
Adiposity
Glucose Tolerance Test
Dyslipidemias
Vasodilator Agents
Oxidants
Knockout Mice
Nitric Oxide Synthase
Endothelium
Breeding
Insulin Resistance
Dilatation
Protein Isoforms
Oxidative Stress
Magnetic Resonance Spectroscopy

Keywords

  • Acetylcholine
  • Animals
  • Insulin resistance
  • Obesity
  • Protein isoforms

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Genetic deletion of NADPH oxidase 1 rescues microvascular function in mice with metabolic disease. / Thompson, Jennifer A.; Larion, Sebastian; Mintz, James D.; Belin de Chantemele, Eric Jacques; Fulton, David J; Stepp, David W.

In: Circulation research, Vol. 121, No. 5, 01.08.2017, p. 502-511.

Research output: Contribution to journalArticle

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