Vascular smooth muscle cells (VSMCs) are indispensable components in foam cell formation in
atherosclerosis. However, the mechanism behind foam cell formation of VSMCs has not been addressed. We found a potential association between deletion of smooth muscle (SM) 22α and deregulated
nuclear receptors liver X receptors (LXRs)/
retinoid X receptor (RXR) signaling in mice. Here, we investigated the roles of SM22α in LXRα-modulated
cholesterol homeostasis, and explore possible mechanisms underlying this process. We identified that the depletion of SM22α was a primary event driving VSMC
cholesterol accumulation and the development of
atherosclerosis in mice. Proteomic and lipidomic analysis validated that downregulation of SM22α was correlated with reduced expression of LXRα and
ATP-binding cassette transporter (ABCA) 1 and increased
cholesteryl ester in phenotypically modulated VSMCs induced by platelets-derived
growth factor (
PDGF)-BB. Notably, LXRα was mainly distributed in the cytoplasm rather than the nucleus in the neointimal and Sm22α-/- VSMCs. Loss of SM22α inhibited the nuclear import of LXRα and reduced ABCA1-mediated
cholesterol efflux via promoting depolymerization of actin stress fibers. Affinity purification and mass spectrometry (AP-MS) analysis, co-immunoprecipitation and GST pull-down assays, confocal microscopy, and stochastic optical reconstruction microscopy (STORM) revealed that globular-actin (
G-actin), monomeric actin, interacted with and retained LXRα in the cytoplasm in
PDGF-BB-treated and Sm22α-/- VSMCs. This interaction blocked LXRα binding to
Importin α, a
karyopherin that mediates the trafficking of macromolecules across the nuclear envelope, and the resulting reduction of LXRα transcriptional activity. Increasing SM22α expression restored nuclear localization of LXRα and removed
cholesterol accumulation via inducing actin polymerization, ameliorating
atherosclerosis. Our findings highlight that LXRα is a mechanosensitive
nuclear receptor and that the nuclear import of LXRα maintained by the SM22α-actin axis is a potential target for blockade of VSMC foam cell formation and development of anti-
atherosclerosis.