Blocking endothelial TRPV4-Nox2 interaction helps reduce ROS production and inflammation, and improves vascular function in obese mice

J Mol Cell Cardiol. 2021 Aug:157:66-76. doi: 10.1016/j.yjmcc.2021.04.008. Epub 2021 Apr 28.

Abstract

Obesity induces inflammation and oxidative stress, and ultimately leads to vasodilatory dysfunction in which Transient receptor potential vanilloid type 4 (TRPV4) and Nicotinamide Adenine Dinucleotide Phosphate Oxidase (Nox2) have been reported to be involved. However, little attention has been paid to the role of the TRPV4-Nox2 complex in these problems. The purpose of this study was to figure out the role of the TRPV4-Nox2 complex in obesity-induced inflammation, oxidative stress, and vasodilatory dysfunction. Using fluorescence resonance energy transfer and immunoprecipitation assays, we found enhanced TRPV4 and Nox2 interactions in obese mice. Using q-PCR, fluorescent dye dihydroethidium staining, and myotonic techniques, we found that obesity caused inflammation, oxidative stress, and vasodilatory dysfunction. Using adeno-associated viruses, we found that enhancement or attenuation of TRPV4-Nox2 interaction altered the vaso-function. Based on these findings, we found a small-molecule drug, M12, that interrupted the TRPV4-Nox2 interaction, thereby reducing inflammatory factors and reactive oxygen species production and helping to restore the vasodilatory function. In summary, our results revealed a new mechanism by which obesity-induced inflammation, oxidative stress, and vasodilatory dysfunction is caused by enhanced TRPV4-Nox2 interactions. Using M12 to interrupt the TRPV4-Nox2 interaction may have anti-inflammatory and anti-oxidative stress effects and help restore vasodilatory function and thus provide a new therapeutic approach to obesity.

Keywords: Inflammation; Obesity; Oxidative stress; Treatment; Vasodilatory dysfunction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers
  • Disease Models, Animal
  • Disease Susceptibility
  • Endothelial Cells / metabolism
  • Endothelium, Vascular / metabolism*
  • Inflammation / etiology*
  • Inflammation / metabolism*
  • Inflammation / pathology
  • Inflammation Mediators / metabolism
  • Mice
  • Mice, Knockout
  • Mice, Obese
  • Mutation
  • NADPH Oxidase 2 / genetics
  • NADPH Oxidase 2 / metabolism*
  • Obesity / complications
  • Obesity / metabolism
  • Oxidative Stress
  • Protein Binding / drug effects
  • Reactive Oxygen Species / metabolism*
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / metabolism*
  • Vasodilation / genetics

Substances

  • Biomarkers
  • Inflammation Mediators
  • Reactive Oxygen Species
  • TRPV Cation Channels
  • Trpv4 protein, mouse
  • Cybb protein, mouse
  • NADPH Oxidase 2