Blocking endothelial TRPV4-Nox2 interaction helps reduce ROS production and inflammation, and improves vascular function in obese mice. (August 2021)

• Record Type: Journal Article
• Authors: Gao, Mengru; Han, Jing; Zhu, Yifei; Tang, Chunlei; Liu, Liangliang; Xiao, Wang; Ma, Xin
• Is Part Of: Journal of molecular and cellular cardiology. Volume 157(2021)
• Page Start: 66
• Page End: 76
• Publication Date: 2021-08
• Subjects: Obesity -- Inflammation -- Oxidative stress -- Vasodilatory dysfunction -- Treatment; TRPV4 transient receptor potential vanilloid 4 -- Nox2 nicotinamide adenine dinucleotide phosphate oxidase -- ROS reactive oxygen species -- WT wild-type -- DIO diet-induced obesity -- BSA bovine serum albumin -- FRET fluorescence resonance energy transfer -- co-IP co-immunoprecipitation -- PFA paraformaldehyde -- CM-H2DCFDA 5, 6-chloromethyl-2′, 7′-dichlorodihydrofluorescein diacetate -- DHE dihydroethidium -- TNF-α tumor necrosis factor-α -- IL-6 interleukin- 6 -- IL-1β interleukin-1β -- AAV adeno-associated virus -- MMAECs primary mouse mesenteric artery endothelial cells -- NO nitric oxide -- M12 N-(5-(3, 5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-methylpiperazin-1-yl)-2-(2, 2, 2-trifluoro-N-(tetrahydro-2H- pyran-4-yl)acetamido)benzamide, C33H33F5N6O3; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2021.04.008
• Languages: English
• ISSNs: 0022-2828

Abstract

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. Graphical abstract: Unlabelled Image Highlights: The interaction between TRPV4 and Nox2 was enhanced in obesity. TRPV4-Nox2 coupling helps regulate ROS production, inflammation and vasodilation. Compound M12 exerts a therapeutic effect by attenuating the TRPV4-Nox2 coupling.