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

Abstract

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.

Mammalian TRP ion channels are insensitive to membrane stretch

“…6A) when expressed in ASH sensory neurons, i.e. the neurons that are required in C. elegans for a wide range of avoidance behaviorsand by stroking the nose of the worm with an eyelash (Caires et al, 2017;Liedtke et al, 2003). OSM-9 is the C. elegans orthologue of mammalian TRPV4; noteworthy, OSM-9 acts downstream of the DEG-1 channel in the ASH-mediated mechanical response (Colbert et al, 1997;Geffeney et al, 2011).We expressed Mus musculus (m)TRPC6 (no TRPC6 ortholog is encoded in the C. elegans genome) in ASH sensory neurons to determine whether TRPC6 can recover the touch response of osm-9 worms (Fig.…”

Endothelial Cell Metabolism in Atherosclerosis

“…Moreover, FAO maintains the cellular pool of acetyl-CoA and retains the identity of vascular ECs by reducing transforming growth factor β-induced endothelial-to-mesenchymal transition (EndMT) (Xiong et al, 2018 ). In addition to its role in EC proliferation, differentiation and permeability, FA metabolism also modulates the lipid composition of EC membranes, thereby regulating membrane stiffness and multiple cellular functions (Caires et al, 2017 ; Glatzel et al, 2018 ; Harayama and Riezman, 2018 ).…”

Neuronal lipolysis participates in PUFA-mediated neural function and neurodegeneration

“…One possibility is that a reduced level of PUFA-containing phospholipids impacts membrane fluidity and in turn reduces ion-channel activity. For example, AA and DHA can regulate channels such as K + channels and TRPV4 (Caires, Sierra-Valdez et al, 2017, Horimoto, Nabekura et al, 1997, Villarroel & Schwarz, 1996. Moreover, phospholipids with PUFAs can be degraded and produce the second messengers 2-AG, 1,2-diacylglycerol and IP3.…”