NADPH oxidase 4 mediates the protective effects of physical activity against obesity-induced vascular dysfunction

Cardiovasc Res. 2020 Aug 1;116(10):1767-1778. doi: 10.1093/cvr/cvz322.

Abstract

Aims: Physical activity is one of the most potent strategies to prevent endothelial dysfunction. Recent evidence suggests vaso-protective properties of hydrogen peroxide (H2O2) produced by main endothelial NADPH oxidase isoform 4 (Nox4) in the vasculature. Therefore, we hypothesized that Nox4 connects physical activity with vaso-protective effects.

Methods and results: Analysis of the endothelial function using Mulvany Myograph showed endothelial dysfunction in wild-type (WT) as well as in C57BL/6J/ Nox4-/- (Nox4-/-) mice after 20 weeks on high-fat diet (HFD). Access to running wheels during the HFD prevented endothelial dysfunction in WT but not in Nox4-/- mice. Mechanistically, exercise led to an increased H2O2 release in the aorta of WT mice with increased phosphorylation of eNOS pathway member AKT serine/threonine kinase 1 (AKT1). Both H2O2 release and phosphorylation of AKT1 were diminished in aortas of Nox4-/- mice. Deletion of Nox4 also resulted in lower intracellular calcium release proven by reduced phenylephrine-mediated contraction, whilst potassium-induced contraction was not affected. H2O2 scavenger catalase reduced phenylephrine-induced contraction in WT mice. Supplementing H2O2 increased phenylephrine-induced contraction in Nox4-/- mice. Exercise-induced peroxisome proliferative-activated receptor gamma, coactivator 1 alpha (Ppargc1a), as key regulator of mitochondria biogenesis in WT but not Nox4-/- mice. Furthermore, exercise-induced citrate synthase activity and mitochondria mass were reduced in the absence of Nox4. Thus, Nox4-/- mice became less active and ran less compared with WT mice.

Conclusions: Nox4 derived H2O2 plays a key role in exercise-induced adaptations of eNOS and Ppargc1a pathway and intracellular calcium release. Hence, loss of Nox4 diminished physical activity performance and vascular protective effects of exercise.

Keywords: Endothelial function; Exercise; NADPH oxidase 4; Nox4; Vascular function; Voluntary running.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Endothelium, Vascular / enzymology*
  • Endothelium, Vascular / physiopathology
  • Hydrogen Peroxide / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / enzymology
  • Mitochondria / pathology
  • NADPH Oxidase 4 / genetics
  • NADPH Oxidase 4 / metabolism*
  • Nitric Oxide Synthase Type III / metabolism
  • Obesity / enzymology
  • Obesity / genetics
  • Obesity / physiopathology
  • Obesity / therapy*
  • Organelle Biogenesis
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
  • Phosphorylation
  • Physical Conditioning, Animal*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Running
  • Signal Transduction
  • Vascular Diseases / enzymology
  • Vascular Diseases / genetics
  • Vascular Diseases / physiopathology
  • Vascular Diseases / prevention & control*
  • Vasoconstriction*

Substances

  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Hydrogen Peroxide
  • Nitric Oxide Synthase Type III
  • Nos3 protein, mouse
  • NADPH Oxidase 4
  • Nox4 protein, mouse
  • Akt1 protein, mouse
  • Proto-Oncogene Proteins c-akt