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Blocking endothelial TRPV4-Nox2 interaction helps reduce ROS production and inflammation, and improves vascular
Mengru Gao1, Jing Han2, Yifei Zhu2
1School of Pharmaceutical Sciences, Jiangnan University, Wuxi, China.
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.
Insights
Obesity worsens inflammation and blood vessel dysfunction by increasing interactions between TRPV4 and Nox2. A new drug, M12, blocks this interaction, reducing damage and restoring blood vessel function.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Obesity Research
Background:
- Obesity is linked to inflammation, oxidative stress, and impaired blood vessel function.
- Transient receptor potential vanilloid type 4 (TRPV4) and Nicotinamide Adenine Dinucleotide Phosphate Oxidase (Nox2) are implicated in these conditions.
- The specific role of the TRPV4-Nox2 complex in obesity-related vascular issues requires further investigation.
Purpose of the Study:
- To elucidate the role of the TRPV4-Nox2 complex in obesity-induced inflammation, oxidative stress, and vasodilatory dysfunction.
- To investigate the therapeutic potential of targeting the TRPV4-Nox2 interaction.
Main Methods:
- Utilized fluorescence resonance energy transfer and immunoprecipitation to assess TRPV4-Nox2 interactions in obese mice.
- Employed quantitative PCR, dihydroethidium staining, and myotonic techniques to evaluate inflammation, oxidative stress, and vascular function.
- Used adeno-associated viruses to modulate TRPV4-Nox2 interactions and assess functional consequences.
- Screened for small-molecule drugs that disrupt the TRPV4-Nox2 complex.
Main Results:
- Obese mice exhibited enhanced interactions between TRPV4 and Nox2.
- Obesity was confirmed to induce significant inflammation, oxidative stress, and vasodilatory dysfunction.
- Modulating TRPV4-Nox2 interactions directly impacted vascular function.
- Identified a small-molecule drug, M12, that effectively interrupts the TRPV4-Nox2 interaction.
Conclusions:
- Enhanced TRPV4-Nox2 interactions represent a novel mechanism driving obesity-induced inflammation, oxidative stress, and vasodilatory dysfunction.
- The drug M12 demonstrates potential therapeutic benefits by reducing inflammation and oxidative stress and restoring vasodilatory function.
- Targeting the TRPV4-Nox2 complex offers a promising new therapeutic strategy for managing obesity-related vascular complications.
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