Smooth muscle LRRC8A knockout reduces O ₂ ^·- influx, inflammation, senescence and atherosclerosis

<b>What Is Known?:</b> Chronically inflamed vascular smooth muscle cells (VSMCs) are critical drivers of atherosclerotic plaque development.In VSMCs, Nox1-derived superoxide drives redox signaling that promotes inflammation, phenotypic switching, and senescence.LRRC8A family volume-regulated anion channels (VRACs) physically associate with Nox1 and support TNFα-induced ROS production, receptor endocytosis, NF-κB activation, and proliferation.Hypercholesterolemia causes VSMC inflammation via oxidized LDL (OxLDL) activation of scavenger receptors (e.g., LOX-1, CD36) that stimulate oxidant production and EGFR/PI3K-Akt-NF-κB signaling.<b>What New Information Does This Article Contribute?:</b> LRRC8A channels support influx of extracellular superoxide which impacts cytosolic redox status, metabolism and Nrf2, HIF-1α, and NF-κB activity.Loss of LRRC8A reprograms VSMCs into a low-oxidative-stress, low-energy-demand state, characterized by diminished proliferation and migration, attenuated senescence, and preservation of telomere length.Loss of LRRC8A inhibits EGF-stimulated EGFR and Akt phosphorylation and uncouples oxidant-dependent growth factor signaling from downstream inflammatory and metabolic remodeling.VSMC-specific LRRC8A knockout or heterozygosity in hypercholesterolemic ApoE⁻/⁻ mice reduces aortic inflammation and senescence, reduces atherosclerotic lesion burden, and preserves mesenteric artery vasomotor function.LRRC8A/VRAC activity is necessary for uptake of oxidized but not native LDL in VSMCs.LRRC8A is a novel regulator of scavenger receptor-dependent lipoprotein handling and a potential therapeutic target to uncouple oxidant signaling from VSMC lipid overload and inflammation in the vessel wall.