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Insulin-independent GLUT4 translocation in proliferative vascular smooth muscle cells involves SM22α

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Abstract

The insulin-sensitive glucose transporter 4 (GLUT4) is a predominant facilitative glucose transporter in vascular smooth muscle cells (VSMCs) and is significantly upregulated in rabbit neointima. This study investigated the role of GLUT4 in VSMC proliferation, the cellular mechanism underlying PDGF-BB-stimulated GLUT4 translocation, and effects of SM22α, an actin-binding protein, on this process. Chronic treatment of VSMCs with PDGF-BB significantly elevated GLUT4 expression and glucose uptake. PDGF-BB-induced VSMC proliferation was dependent on GLUT4-mediated glucose uptake. Meanwhile, the response of GLUT4 to insulin decreased in PDGF-BB-stimulated VSMCs. PDGF-BB-induced GLUT4 translocation partially rescued glucose utilization in insulin-resistant cells. Immunofluorescence and western blot analysis revealed that PDGF-BB induced GLUT4 translocation in an actin dynamics-dependent manner. SM22α disruption facilitated GLUT4 translocation and glucose uptake by promoting actin dynamics and cortical actin polymerization. Similar results were observed in VSMCs of SM22α −/− mice. The in vivo experiments showed that the glucose level in the neointima induced by ligation was significantly increased in SM22α −/− mice, accompanied by increased neointimal thickness, compared with those in wild-type mice. These findings suggest that GLUT4-mediated glucose uptake is involved in VSMC proliferation, and provide a novel link between SM22α and glucose utilization in PDGF-BB-triggered proliferation.

Key Messages

• GLUT4-mediated glucose uptake is required for the VSMC proliferation.

• PDGF-BB-induced GLUT4 translocation partially rescues glucose uptake in insulin resistance.

• SM22α disruption enhances PDGF-BB-induced GLUT4 translocation.

• Glucose level in injured vascular tissue is positively correlated with neointimal hyperplasia.

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References

  1. Kornowski R, Mintz GS, Kent KM, Pichard AD, Satler LF, Bucher TA, Hong MK, Popma JJ, Leon MB (1997) Increased restenosis in diabetes mellitus after coronary interventions is due to exaggerated intimal hyperplasia. A serial intravascular ultrasound study. Circulation 95:1366–1369

    Article  CAS  PubMed  Google Scholar 

  2. Brand FN, Abbott RD, Kannel WB (1989) Diabetes, intermittent claudication, and risk of cardiovascular events. The Framingham Study. Diabetes 38:504–509

    Article  CAS  PubMed  Google Scholar 

  3. Vander Heiden MG, Plas DR, Rathmell JC, Fox CJ, Harris MH, Thompson CB (2001) Growth factors can influence cell growth and survival through effects on glucose metabolism. Mol Cell Biol 21:5899–5912

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Werle M, Kreuzer J, Höfele J, Elsässer A, Ackermann C, Katus HA, Vogt AM (2005) Metabolic control analysis of the Warburg-effect in proliferating vascular smooth muscle cells. J Biomed Sci 12:827–834

    Article  CAS  PubMed  Google Scholar 

  5. Perez J, Hill B, Benavides G, Dranka B, Darley-Usmar V (2010) Role of cellular bioenergetics in smooth muscle cell proliferation induced by platelet-derived growth factor. Biochem J 428:255–267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Park JL, Loberg RD, Duquaine D, Zhang H, Deo BK, Ardanaz N, Coyle J, Atkins KB, Schin M, Charron MJ, et al. (2005) GLUT4 facilitative glucose transporter specifically and differentially contributes to agonist-induced vascular reactivity in mouse aorta. Arterioscler Thromb Vasc Biol 25:1596–1602

    Article  CAS  PubMed  Google Scholar 

  7. Hall JL, Chatham JC, Eldar-Finkelman H, Gibbons GH (2001) Upregulation of glucose metabolism during intimal lesion formation is coupled to the inhibition of vascular smooth muscle cell apoptosis role of GSK3β. Diabetes 50:1171–1179

    Article  CAS  PubMed  Google Scholar 

  8. Zhao Y, Biswas SK, McNulty PH, Kozak M, Jun JY, Segar L (2011) PDGF-induced vascular smooth muscle cell proliferation is associated with dysregulation of insulin receptor substrates. Am J Physiol Cell Physiol 300:C1375–C1385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Rosenblatt-Velin N, Lerch R, Papageorgiou I, Montessuit C (2004) Insulin resistance in adult cardiomyocytes undergoing dedifferentiation: role of GLUT4 expression and translocation. FASEB J 18:872–874

    CAS  PubMed  Google Scholar 

  10. Yuasa T, Kakuhata R, Kishi K, Obata T, Shinohara Y, Bando Y, Izumi K, Kajiura F, Matsumoto M, Ebina Y (2004) Platelet-derived growth factor stimulates glucose transport in skeletal muscles of transgenic mice specifically expressing platelet-derived growth factor receptor in the muscle, but it does not affect blood glucose levels. Diabetes 53:2776–2786

    Article  CAS  PubMed  Google Scholar 

  11. Khayat ZA, Tong P, Yaworsky K, Bloch RJ, Klip A (2000) Insulin-induced actin filament remodeling colocalizes actin with phosphatidylinositol 3-kinase and GLUT4 in L6 myotubes. J Cell Sci 113:279–290

    CAS  PubMed  Google Scholar 

  12. Roya H-R, Lena C-W, Stefan W, Koutaro Y, Agneta S, Carl-Henrik H (1997) Involvement of phosphatidylinositide 3′-kinase and Rac in platelet-derived growth factor-induced actin reorganization and chemotaxis. Exp Cell Res 234:434–441

    Article  Google Scholar 

  13. Yu K, Zheng B, Han M, Wen J-K (2011) ATRA activates and PDGF-BB represses the SM22alpha promoter through KLF4 binding to, or dissociating from, its cis-DNA elements. Cardiovasc Res 90:464–474

    Article  CAS  PubMed  Google Scholar 

  14. Fu Y, Liu H-W, Forsythe SM, Kogut P, McConville JF, Halayko AJ, Camoretti-Mercado B, Solway J (2000) Mutagenesis analysis of human SM22: characterization of actin binding. J Appl Physiol 89:1985–1990

    CAS  PubMed  Google Scholar 

  15. Kobayashi R, Kubota T, Hidaka H (1994) Purification, characterization, and partial sequence-analysis of a new 25-kDa actin-binding protein from bovine aorta: a SM22 homolog. Biochem Biophys Res Commun 198:1275–1280

    Article  CAS  PubMed  Google Scholar 

  16. Han M, Dong L-H, Zheng B, Shi J-H, Wen J-K, Cheng Y (2009) Smooth muscle 22 alpha maintains the differentiated phenotype of vascular smooth muscle cells by inducing filamentous actin bundling. Life Sci 84:394–401

    Article  CAS  PubMed  Google Scholar 

  17. Yang M, Jiang H, Li L (2010) Sm22alpha transcription occurs at the early onset of the cardiovascular system and the intron 1 is dispensable for its transcription in smooth muscle cells during mouse development. Int J Physiol Pathophysiol Pharmacol 2:12–19

    PubMed  Google Scholar 

  18. Xie X-L, Liu Y-B, Liu Y-P, B-L D, Li Y, Han M, Li B-H (2013) Reduced expression of SM22 is correlated with low autophagy activity in human colorectal cancer. Pathol Res Pract 209:237–243

    Article  CAS  PubMed  Google Scholar 

  19. Xie X-L, Nie X, Wu J, Zhang F, Zhao L-L, Lin Y-L, Yin Y-J, Liu H, Shu Y-N, Miao S-B, Li H, Chen P, Han M (2015) Smooth muscle 22α facilitates angiotensin II-induced signaling and vascular contraction. J Mol Med (Berl) 93:547–558

    Article  CAS  Google Scholar 

  20. Feil S, Hofmann F, Feil R (2004) SM22α modulates vascular smooth muscle cell phenotype during atherogenesis. Circ Res 94:863–865

    Article  CAS  PubMed  Google Scholar 

  21. Dong L-H, Wen J-K, Liu G, McNutt MA, Miao S-B, Gao R, Zheng B, Zhang H, Han M (2010) Blockade of the Ras–extracellular signal–regulated kinase 1/2 pathway is involved in smooth muscle 22α–mediated suppression of vascular smooth muscle cell proliferation and neointima hyperplasia. Arterioscler Thromb Vasc Biol 30:683–691

    Article  CAS  PubMed  Google Scholar 

  22. Thompson O, Moghraby JS, Ayscough KR, Winder SJ (2012) Depletion of the actin bundling protein SM22/transgelin increases actin dynamics and enhances the tumourigenic phenotypes of cells. BMC Cell Biol 13:1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhang J, Zhong W, Cui T, Yang M, Hu X, Xu K, Xie C, Xue C, Gibbons GH, Liu C, et al. (2006) Generation of an adult smooth muscle cell-targeted Cre recombinase mouse model. Arterioscler Thromb Vasc Biol 26:e23–e24

    PubMed  PubMed Central  Google Scholar 

  24. Kumar A, Lindner V (1997) Remodeling with neointima formation in the mouse carotid artery after cessation of blood flow. Arterioscler Thromb Vasc Biol 17:2238–2244

    Article  CAS  PubMed  Google Scholar 

  25. Shu Y-N, Zhang F, Bi W, Dong L-H, Zhang D-D, Chen R, Lv P, Xie X-L, Lin Y-L, Xue Z-Y, et al. (2015) SM22α inhibits vascular inflammation via stabilization of IκBα in vascular smooth muscle cells. J Mol Cell Cardiol 84:191–199

    Article  CAS  PubMed  Google Scholar 

  26. S-M Y, Tsai SY, Guh JH, Ko FN, Teng CM, JT O (1996) Mechanism of catecholamine-induced proliferation of vascular smooth muscle cells. Circulation 94:547–554

    Article  Google Scholar 

  27. Merry TL, Steinberg GR, Lynch GS, McConell GK (2010) Skeletal muscle glucose uptake during contraction is regulated by nitric oxide and ROS independently of AMPK. Am J Physiol Endocrinol Metab 298:E577–E585

  28. Zhang W-Y, Lee JJ, Kim IS, Kim Y, Park JS, Myung CS (2010) 7-O-Methylaromadendrin stimulates glucose uptake and improves insulin resistance in vitro. Biol Pharm Bull 33:1494–1499

    Article  CAS  PubMed  Google Scholar 

  29. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  30. Liu X-J, Yang C, Nishith G, Zuo J, Chang Y-S, Fang F-D (2007) Protein kinase C-ζ regulation of GLUT4 translocation through actin remodeling in CHO cells. J Mol Med 85:851–861

    CAS  PubMed  Google Scholar 

  31. Gao D, Madi M, Ding C, Fok M, Steele T, Ford C, Hunter L, Bing C (2014) Interleukin-1beta mediates macrophage-induced impairment of insulin signaling in human primary adipocytes. Am J Physiol Endocrinol Metab 307:E289–E304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Leto D, Saltiel AR (2012) Regulation of glucose transport by insulin: traffic control of GLUT4. Nat Rev Mol Cell Biol 3:383–396

    Article  Google Scholar 

  33. Tong P, Khayat ZA, Huang C, Patel N, Ueyama A, Klip A (2001) Insulin-induced cortical actin remodeling promotes GLUT4 insertion at muscle cell membrane ruffles. J Clin Invest 108:371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kamohara S, Hayashi H, Todaka M, Kanai F, Ishii K, Imanaka T, Escobedo JA, Williams LT, Ebina Y (1995) Platelet-derived growth factor triggers translocation of the insulin-regulatable glucose transporter (type 4) predominantly through phosphatidylinositol 3-kinase binding sites on the receptor. Proc Natl Acad Sci U S A 92:1077–1081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang L, Hayashi H, Ebina Y (1999) Transient effect of platelet-derived growth factor on GLUT4 translocation in 3T3-L1 adipocytes. J Biol Chem 274:19246–19253

    Article  CAS  PubMed  Google Scholar 

  36. Osorio-Fuentealba C, Contreras-Ferrat AE, Altamirano F, Espinosa A, Li Q, Niu W, Lavandero S, Klip A, Jaimovich E (2013) Electrical stimuli release ATP to increase GLUT4 translocation and glucose uptake via PI3Kgamma-Akt-AS160 in skeletal muscle cells. Diabetes 62:1519–1526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dong L-H, Li L, Song Y, Duan Z-L, Sun S-G, Lin Y-L, Miao S-B, Yin Y-J, Shu Y-N, Li H, et al. (2015) TRAF6-mediated SM22alpha K21 ubiquitination promotes G6PD activation and NADPH production, contributing to GSH homeostasis and VSMC survival in vitro and in vivo. Circ Res 117:684–694

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China 91439114, 31471092 and 31271222 (to M.H.), and 31401199 (to F.Z.), 31571176 (to L.N.), and 81300225 (to P.L.).

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Authors and Affiliations

  1. Key Laboratory of Medical Biotechnology of Hebei Province, Department of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang, 050017, People’s Republic of China

    Li-Li Zhao, Fan Zhang, Peng Chen, Xiao-Li Xie, Yong-Qing Dou, Yan-Ling Lin, Lei Nie, Pin Lv, Dan-Dan Zhang, Xiao-Kun Li, Sui-Bing Miao, Ya-Juan Yin, Li-Hua Dong, Yu Song, Ya-Nan Shu & Mei Han

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  1. Li-Li Zhao
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Correspondence to Mei Han.

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Zhao, LL., Zhang, F., Chen, P. et al. Insulin-independent GLUT4 translocation in proliferative vascular smooth muscle cells involves SM22α. J Mol Med 95, 181–192 (2017). https://doi.org/10.1007/s00109-016-1468-2

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  • DOI: https://doi.org/10.1007/s00109-016-1468-2

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