| First Author | Zhang DD | Year | 2021 |
| Journal | Cell Death Dis | Volume | 12 |
| Issue | 11 | Pages | 982 |
| PubMed ID | 34686657 | Mgi Jnum | J:312853 |
| Mgi Id | MGI:6792119 | Doi | 10.1038/s41419-021-04239-w |
| Citation | Zhang DD, et al. (2021) Smooth muscle 22 alpha protein inhibits VSMC foam cell formation by supporting normal LXRalpha signaling, ameliorating atherosclerosis. Cell Death Dis 12(11):982 |
| abstractText | 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) 22alpha and deregulated nuclear receptors liver X receptors (LXRs)/retinoid X receptor (RXR) signaling in mice. Here, we investigated the roles of SM22alpha in LXRalpha-modulated cholesterol homeostasis, and explore possible mechanisms underlying this process. We identified that the depletion of SM22alpha was a primary event driving VSMC cholesterol accumulation and the development of atherosclerosis in mice. Proteomic and lipidomic analysis validated that downregulation of SM22alpha was correlated with reduced expression of LXRalpha and ATP-binding cassette transporter (ABCA) 1 and increased cholesteryl ester in phenotypically modulated VSMCs induced by platelets-derived growth factor (PDGF)-BB. Notably, LXRalpha was mainly distributed in the cytoplasm rather than the nucleus in the neointimal and Sm22alpha(-/-) VSMCs. Loss of SM22alpha inhibited the nuclear import of LXRalpha 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 LXRalpha in the cytoplasm in PDGF-BB-treated and Sm22alpha(-/-) VSMCs. This interaction blocked LXRalpha binding to Importin alpha, a karyopherin that mediates the trafficking of macromolecules across the nuclear envelope, and the resulting reduction of LXRalpha transcriptional activity. Increasing SM22alpha expression restored nuclear localization of LXRalpha and removed cholesterol accumulation via inducing actin polymerization, ameliorating atherosclerosis. Our findings highlight that LXRalpha is a mechanosensitive nuclear receptor and that the nuclear import of LXRalpha maintained by the SM22alpha-actin axis is a potential target for blockade of VSMC foam cell formation and development of anti-atherosclerosis. |
