Plasma Membrane Localization of CD36 Requires Vimentin Phosphorylation; A Mechanism by Which Macrophage Vimentin Promotes Atherosclerosis

Vimentin is a type III intermediate filament protein expressed in cells of mesenchymal origin. Vimentin has been thought to function mainly as a structural protein and roles of vimentin in other cellular processes have not been extensively studied. Our current study aims to reveal functions of vimentin in macrophage foam cell formation, the critical stage of atherosclerosis. We demonstrated that vimentin null (Vim–/–) mouse peritoneal macrophages take up less oxidized LDL (oxLDL) than vimentin wild type (Vim+/+) macrophages. Despite less uptake of oxLDL in Vim–/– macrophages, Vim+/+ and Vim–/– macrophages did not show difference in expression of CD36 known to mediate oxLDL uptake. However, CD36 localized in plasma membrane was 50% less in Vim–/– macrophages than in Vim+/+ macrophages. OxLDL/CD36 interaction induced protein kinase A (PKA)-mediated vimentin (Ser72) phosphorylation. Cd36–/– macrophages did not exhibit vimentin phosphorylation (Ser72) in response to oxLDL. Experiments using phospho-mimetic mutation of vimentin revealed that macrophages with aspartate-substituted vimentin (V72D) showed more oxLDL uptake and membrane CD36. LDL receptor null (Ldlr–/–) mice reconstituted with Vim–/– bone marrow fed a western diet for 15 weeks showed 43% less atherosclerotic lesion formation than Ldlr–/– mice with Vim+/+ bone marrow. In addition, Apoe–/–Vim–/– (double null) mice fed a western diet for 15 weeks also showed 57% less atherosclerotic lesion formation than Apoe–/– and Vim+/+mice. We concluded that oxLDL via CD36 induces PKA-mediated phosphorylation of vimentin (Ser72) and phosphorylated vimentin (Ser72) directs CD36 trafficking to plasma membrane in macrophages. This study reveals a function of vimentin in CD36 trafficking and macrophage foam cell formation and may guide to establish a new strategy for the treatment of atherosclerosis.

[1]  G. Oh,et al.  Vimentin Deficiency Prevents High-Fat Diet-Induced Obesity and Insulin Resistance in Mice , 2020, Diabetes & metabolism journal.

[2]  Huiling Guo,et al.  DHHC4 and DHHC5 Facilitate Fatty Acid Uptake by Palmitoylating and Targeting CD36 to the Plasma Membrane. , 2019, Cell reports.

[3]  J. Borén,et al.  Vimentin deficiency in macrophages induces increased oxidative stress and vascular inflammation but attenuates atherosclerosis in mice , 2018, Scientific Reports.

[4]  L. Nielsen,et al.  Bone marrow-derived and peritoneal macrophages have different inflammatory response to oxLDL and M1/M2 marker expression – implications for atherosclerosis research , 2016, Scientific Reports.

[5]  Guoliang Meng,et al.  The inhibition of macrophage foam cell formation by tetrahydroxystilbene glucoside is driven by suppressing vimentin cytoskeleton. , 2016, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[6]  Jihong Han,et al.  Inhibition of Macrophage CD36 Expression and Cellular Oxidized Low Density Lipoprotein (oxLDL) Accumulation by Tamoxifen , 2016, The Journal of Biological Chemistry.

[7]  J. Goldstein,et al.  Identification of NPC1 as the target of U18666A, an inhibitor of lysosomal cholesterol export and Ebola infection , 2015, eLife.

[8]  Juhyun Song,et al.  PKA Inhibitor H89 (N-[2-p-bromocinnamylamino-ethyl]-5-isoquinolinesulfonamide) Attenuates Synaptic Dysfunction and Neuronal Cell Death following Ischemic Injury , 2015, Neural plasticity.

[9]  K. Bibbins-Domingo,et al.  Global Overview of the Epidemiology of Atherosclerotic Cardiovascular Disease. , 2015, Archives of medical research.

[10]  F. Cañada,et al.  Vimentin filament organization and stress sensing depend on its single cysteine residue and zinc binding , 2015, Nature Communications.

[11]  Young Mi Park.  CD36, a scavenger receptor implicated in atherosclerosis , 2014, Experimental & Molecular Medicine.

[12]  W. Franke,et al.  On the Formation of Lipid Droplets in Human Adipocytes: The Organization of the Perilipin–Vimentin Cortex , 2014, PloS one.

[13]  Justin Jang Hann Chu,et al.  Cellular Vimentin Regulates Construction of Dengue Virus Replication Complexes through Interaction with NS4A Protein , 2013, Journal of Virology.

[14]  N. Pante,et al.  The intermediate filament network protein, vimentin, is required for parvoviral infection. , 2013, Virology.

[15]  Bart Lammers,et al.  ATP-binding cassette transporters A1 and G1, HDL metabolism, cholesterol efflux, and inflammation: important targets for the treatment of atherosclerosis. , 2011, Current drug targets.

[16]  Y. Huang,et al.  Evaluation of foam cell formation in cultured macrophages: an improved method with Oil Red O staining and DiI-oxLDL uptake , 2010, Cytotechnology.

[17]  F. Nakamura,et al.  Regulation of cell adhesion to collagen via beta1 integrins is dependent on interactions of filamin A with vimentin and protein kinase C epsilon. , 2010, Experimental cell research.

[18]  R. Goldman,et al.  Vimentin induces changes in cell shape, motility, and adhesion during the epithelial to mesenchymal transition , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[19]  U. Aebi,et al.  Intermediate filaments: primary determinants of cell architecture and plasticity. , 2009, The Journal of clinical investigation.

[20]  A. Minin,et al.  Intermediate vimentin filaments and their role in intracellular organelle distribution , 2008, Biochemistry (Moscow).

[21]  M. Connelly,et al.  Distinct mechanisms for OxLDL uptake and cellular trafficking by class B scavenger receptors CD36 and SR-BI Published, JLR Papers in Press, September 19, 2007. , 2007, Journal of Lipid Research.

[22]  Ueli Aebi,et al.  Towards a molecular description of intermediate filament structure and assembly. , 2007, Experimental cell research.

[23]  Kathleen A. Kennedy,et al.  Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4 , 2006, Nature.

[24]  S. Hazen,et al.  A CD36‐dependent signaling cascade is necessary for macrophage foam cell formation , 2006, Cell metabolism.

[25]  M. Inagaki,et al.  PKCε‐mediated phosphorylation of vimentin controls integrin recycling and motility , 2005 .

[26]  M. Inagaki,et al.  Phosphorylation by Cdk1 induces Plk1-mediated vimentin phosphorylation during mitosis , 2005, The Journal of cell biology.

[27]  A. Davies,et al.  ABCA1 and atherosclerosis , 2005, Vascular medicine.

[28]  V. Faundez,et al.  The endo-lysosomal sorting machinery interacts with the intermediate filament cytoskeleton. , 2004, Molecular biology of the cell.

[29]  Robert D Goldman,et al.  Specific in vivo phosphorylation sites determine the assembly dynamics of vimentin intermediate filaments , 2004, Journal of Cell Science.

[30]  P. Libby.  Inflammation in atherosclerosis , 2002, Nature.

[31]  R. Buckland,et al.  The terminal six amino-acids of the carboxy cytoplasmic tail of CD36 contain a functional domain implicated in the binding and capture of oxidized low-density lipoprotein. , 2002, The Biochemical journal.

[32]  K. Higaki,et al.  Accumulation of cholera toxin and GM1 ganglioside in the early endosome of Niemann–Pick C1-deficient cells , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[33]  Christopher K. Glass,et al.  Atherosclerosis The Road Ahead , 2001, Cell.

[34]  Roy L. Silverstein,et al.  CD36 and atherosclerosis , 2000, Current opinion in lipidology.

[35]  S. Hazen,et al.  Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice. , 2000, The Journal of clinical investigation.

[36]  M. Hofker,et al.  Scavenging new insights into atherogenesis. , 2000, The Journal of clinical investigation.

[37]  S. Hazen,et al.  Macrophage scavenger receptor CD36 is the major receptor for LDL modified by monocyte-generated reactive nitrogen species. , 2000, The Journal of clinical investigation.

[38]  S. Hazen,et al.  Myeloperoxidase-generated reactive nitrogen species convert LDL into an atherogenic form in vitro. , 1999, The Journal of clinical investigation.

[39]  D. Ingber,et al.  Impaired mechanical stability, migration and contractile capacity in vimentin-deficient fibroblasts. , 1998, Journal of cell science.

[40]  R. Evans,et al.  Oxidized LDL Regulates Macrophage Gene Expression through Ligand Activation of PPARγ , 1998, Cell.

[41]  Jihong Han,et al.  Native and Modified Low Density Lipoproteins Increase the Functional Expression of the Macrophage Class B Scavenger Receptor, CD36* , 1997, The Journal of Biological Chemistry.

[42]  K. G. Coleman,et al.  Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. , 1997, Science.

[43]  J. Lieber,et al.  Disruption of the vimentin intermediate filament system during adipose conversion of 3T3-L1 cells inhibits lipid droplet accumulation. , 1996, Journal of cell science.

[44]  M. Inagaki,et al.  Visualization and function of vimentin phosphorylation by cdc2 kinase during mitosis. , 1994, Journal of Biological Chemistry.

[45]  C. Babinet,et al.  Mice lacking vimentin develop and reproduce without an obvious phenotype , 1994, Cell.

[46]  W D Wagner,et al.  A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.

[47]  L. Stanton,et al.  CD36 is a receptor for oxidized low density lipoprotein. , 1993, The Journal of biological chemistry.

[48]  S. Panini,et al.  A functional role for vimentin intermediate filaments in the metabolism of lipoprotein-derived cholesterol in human SW-13 cells. , 1992, The Journal of biological chemistry.

[49]  C. Grund,et al.  Rearrangement of the vimentin cytoskeleton during adipose conversion: Formation of an intermediate filament cage around lipid globules , 1987, Cell.

[50]  R. Silverstein,et al.  Mechanisms of cell signaling by the scavenger receptor CD36: implications in atherosclerosis and thrombosis. , 2010, Transactions of the American Clinical and Climatological Association.

[51]  R. Stricter,et al.  Macrophage , 1998, AccessScience.

[52]  K Weber,et al.  Intermediate filaments: structure, dynamics, function, and disease. , 1994, Annual review of biochemistry.

[53]  H. CStary,et al.  A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. , 1994 .

[54]  T. Katsumoto,et al.  The role of the vimentin intermediate filaments in rat 3Y1 cells elucidated by immunoelectron microscopy and computer‐graphic reconstruction , 1990, Biology of the cell.

[55]  F. Hatch.  Practical methods for plasma lipoprotein analysis. , 1968, Advances in lipid research.