Omega-3 Fatty Acids Modulate TRPV4 Function through Plasma Membrane Remodeling

• Published in: Cell reports (Cambridge) 2017-10, Vol.21 (1), p.246-258
• Main Authors: Caires, Rebeca, Sierra-Valdez, Francisco J., Millet, Jonathan R.M., Herwig, Joshua D., Roan, Esra, Vásquez, Valeria, Cordero-Morales, Julio F.
• Format: Article
• Language: English
• Subjects: 17,18-epoxyeicosatetraenoic acid; Animals; Animals, Genetically Modified; Antihypertensive Agents - metabolism; Antihypertensive Agents - pharmacology; atomic force microscopy; Caenorhabditis elegans; Caenorhabditis elegans - drug effects; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Cell Line; Cell Membrane - chemistry; Cell Membrane - drug effects; Cell Membrane - metabolism; eicosapentaenoic acid; endothelial cells; Endothelial Cells - cytology; Endothelial Cells - drug effects; Endothelial Cells - metabolism; fatty acids; Fatty Acids, Omega-3 - metabolism; Fatty Acids, Omega-3 - pharmacology; Gene Expression; Humans; Lipid Metabolism - drug effects; Membrane Fluidity - drug effects; Metabolome; neurons; Phorbols - pharmacology; Phospholipids - metabolism; polyunsaturated fatty acids; TRP channels; TRPV Cation Channels - agonists; TRPV Cation Channels - genetics; TRPV Cation Channels - metabolism; TRPV4
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.09.029

Dietary consumption of ω-3 polyunsaturated fatty acids (PUFAs), present in fish oils, is known to improve the vascular response, but their molecular targets remain largely unknown. Activation of the TRPV4 channel has been implicated in endothelium-dependent vasorelaxation. Here, we studied the contribution of ω-3 PUFAs to TRPV4 function by precisely manipulating the fatty acid content in Caenorhabditis elegans. By genetically depriving the worms of PUFAs, we determined that the metabolism of ω-3 fatty acids is required for TRPV4 activity. Functional, lipid metabolome, and biophysical analyses demonstrated that ω-3 PUFAs enhance TRPV4 function in human endothelial cells and support the hypothesis that lipid metabolism and membrane remodeling regulate cell reactivity. We propose a model whereby the eicosanoid’s epoxide group location increases membrane fluidity and influences the endothelial cell response by increasing TRPV4 channel activity. ω-3 PUFA-like molecules might be viable antihypertensive agents for targeting TRPV4 to reduce systemic blood pressure. [Display omitted] •TRPV4 activity is modulated by dietary ω-3 polyunsaturated fatty acids•ω-3 eicosanoid epoxide derivatives are required for TRPV4 function in worm neurons•Eicosapentaenoic acid enhances TRPV4 activity in human endothelial cells•ω-3 fatty acid derivatives increase fluidity of endothelial cell plasma membranes Dietary ω-3 fatty acids have beneficial cardiovascular effects, but their molecular targets remain largely unknown. Caires et al. show that ω-3 fatty acids increase plasma membrane fluidity and enhance TRPV4 function in human endothelial cells, whose activation reduces systemic blood pressure.