The Korean Journal of Physiology and Pharmacology

  • 제21권1호
  • /
  • Pages.37-44
  • /
  • 2017
  • /
  • 1226-4512(pISSN)
  • /
  • 2093-3827(eISSN)
대한약리학회 (The Korean Society of Pharmacology)
권호 표지
DOI QR코드

DOI QR Code

Regulation of vascular smooth muscle phenotype by cross-regulation of krüppel-like factors

  • Ha, Jung Min (Gene and Cell Therapy for Vessel-Associated Disease, Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine) ;
  • Yun, Sung Ji (Gene and Cell Therapy for Vessel-Associated Disease, Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine) ;
  • Jin, Seo Yeon (Gene and Cell Therapy for Vessel-Associated Disease, Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine) ;
  • Lee, Hye Sun (Gene and Cell Therapy for Vessel-Associated Disease, Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine) ;
  • Kim, Sun Ja (Department of Physics, Dong-A University) ;
  • Shin, Hwa Kyoung (Department of Anatomy, Pusan National University School of Korean Medicine) ;
  • Bae, Sun Sik (Gene and Cell Therapy for Vessel-Associated Disease, Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine)
  • 투고 : 2016.06.26
  • 심사 : 2016.08.18
  • 발행 : 2017.01.01
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Regulation of vascular smooth muscle cell (VSMC) phenotype plays an essential role in many cardiovascular diseases. In the present study, we provide evidence that $kr{\ddot{u}}ppel$-like factor 8 (KLF8) is essential for tumor necrosis factor ${\alpha}$ ($TNF{\alpha}$)-induced phenotypic conversion of VSMC obtained from thoracic aorta from 4-week-old SD rats. Stimulation of the contractile phenotype of VSMCs with $TNF{\alpha}$ significantly reduced the VSMC marker gene expression and KLF8. The gene expression of KLF8 was blocked by $TNF{\alpha}$ stimulation in an ERK-dependent manner. The promoter region of KLF8 contained putative Sp1, KLF4, and $NF{\kappa}B$ binding sites. Myocardin significantly enhanced the promoter activity of KLF4 and KLF8. The ectopic expression of KLF4 strongly enhanced the promoter activity of KLF8. Moreover, silencing of Akt1 significantly attenuated the promoter activity of KLF8; conversely, the overexpression of Akt1 significantly enhanced the promoter activity of KLF8. The promoter activity of SMA, $SM22{\alpha}$, and KLF8 was significantly elevated in the contractile phenotype of VSMCs. The ectopic expression of KLF8 markedly enhanced the expression of SMA and $SM22{\alpha}$ concomitant with morphological changes. The overexpression of KLF8 stimulated the promoter activity of SMA. Stimulation of VSMCs with $TNF{\alpha}$ enhanced the expression of KLF5, and the promoter activity of KLF5 was markedly suppressed by KLF8 ectopic expression. Finally, the overexpression of KLF5 suppressed the promoter activity of SMA and $SM22{\alpha}$, thereby reduced the contractility in response to the stimulation of angiotensin II. These results suggest that cross-regulation of KLF family of transcription factors plays an essential role in the VSMC phenotype.

키워드

참고문헌

  1. Owens GK. Regulation of differentiation of vascular smooth muscle cells. Physiol Rev. 1995;75:487-517. https://doi.org/10.1152/physrev.1995.75.3.487
  2. Wynne BM, Chiao CW, Webb RC. Vascular smooth muscle cell signaling mechanisms for contraction to angiotensin ii and endothelin-1. J Am Soc Hypertens. 2009;3:84-95. https://doi.org/10.1016/j.jash.2008.09.002
  3. Owens GK, Kumar MS, Wamhoff BR. Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev. 2004;84:767-801. https://doi.org/10.1152/physrev.00041.2003
  4. McConnell BB, Yang VW. Mammalian Kruppel-like factors in health and diseases. Physiol Rev. 2010;90:1337-1381. https://doi.org/10.1152/physrev.00058.2009
  5. Haldar SM, Ibrahim OA, Jain MK. Kruppel-like factors (KLFs) in muscle biology. J Mol Cell Cardiol. 2007;43:1-10. https://doi.org/10.1016/j.yjmcc.2007.04.005
  6. Evans PM, Zhang W, Chen X, Yang J, Bhakat KK, Liu C. Kruppellike factor 4 is acetylated by p300 and regulates gene transcription via modulation of histone acetylation. J Biol Chem. 2007;282:33994-34002. https://doi.org/10.1074/jbc.M701847200
  7. Miyamoto S, Suzuki T, Muto S, Aizawa K, Kimura A, Mizuno Y, Nagino T, Imai Y, Adachi N, Horikoshi M, Nagai R. Positive and negative regulation of the cardiovascular transcription factor KLF5 by p300 and the oncogenic regulator SET through interaction and acetylation on the DNA-binding domain. Mol Cell Biol. 2003; 23:8528-8541. https://doi.org/10.1128/MCB.23.23.8528-8541.2003
  8. Matsumura T, Suzuki T, Aizawa K, Munemasa Y, Muto S, Horikoshi M, Nagai R. The deacetylase HDAC1 negatively regulates the cardiovascular transcription factor Kruppel-like factor 5 through direct interaction. J Biol Chem. 2005;280:12123-12129. https://doi.org/10.1074/jbc.M410578200
  9. Meng F, Han M, Zheng B, Wang C, Zhang R, Zhang XH, Wen JK. All-trans retinoic acid increases KLF4 acetylation by inducing HDAC2 phosphorylation and its dissociation from KLF4 in vascular smooth muscle cells. Biochem Biophys Res Commun. 2009;387:13-18. https://doi.org/10.1016/j.bbrc.2009.05.112
  10. He M, Han M, Zheng B, Shu YN, Wen JK. Angiotensin II stimulates KLF5 phosphorylation and its interaction with c-Jun leading to suppression of p21 expression in vascular smooth muscle cells. J Biochem. 2009;146:683-691. https://doi.org/10.1093/jb/mvp115
  11. Oishi Y, Manabe I, Tobe K, Ohsugi M, Kubota T, Fujiu K, Maemura K, Kubota N, Kadowaki T, Nagai R. SUMOylation of Kruppel-like transcription factor 5 acts as a molecular switch in transcriptional programs of lipid metabolism involving PPAR-delta. Nat Med. 2008;14:656-666. https://doi.org/10.1038/nm1756
  12. Chen ZY, Wang X, Zhou Y, Offner G, Tseng CC. Destabilization of Kruppel-like factor 4 protein in response to serum stimulation involves the ubiquitin-proteasome pathway. Cancer Res. 2005; 65:10394-10400. https://doi.org/10.1158/0008-5472.CAN-05-2059
  13. Chen C, Sun X, Ran Q, Wilkinson KD, Murphy TJ, Simons JW, Dong JT. Ubiquitin-proteasome degradation of KLF5 transcription factor in cancer and untransformed epithelial cells. Oncogene. 2005;24:3319-3327. https://doi.org/10.1038/sj.onc.1208497
  14. Du JX, Yun CC, Bialkowska A, Yang VW. Protein inhibitor of activated STAT1 interacts with and up-regulates activities of the pro-proliferative transcription factor Kruppel-like factor 5. J Biol Chem. 2007;282:4782-4793. https://doi.org/10.1074/jbc.M603413200
  15. Kawai-Kowase K, Kumar MS, Hoofnagle MH, Yoshida T, Owens GK. PIAS1 activates the expression of smooth muscle cell differentiation marker genes by interacting with serum response factor and class I basic helix-loop-helix proteins. Mol Cell Biol. 2005;25:8009-8023. https://doi.org/10.1128/MCB.25.18.8009-8023.2005
  16. Du JX, Bialkowska AB, McConnell BB, Yang VW. SUMOylation regulates nuclear localization of Kruppel-like factor 5. J Biol Chem. 2008;283:31991-32002. https://doi.org/10.1074/jbc.M803612200
  17. Beamish JA, He P, Kottke-Marchant K, Marchant RE. Molecular regulation of contractile smooth muscle cell phenotype: implications for vascular tissue engineering. Tissue Eng Part B Rev. 2010;16:467-491. https://doi.org/10.1089/ten.teb.2009.0630
  18. Kober F, Canault M, Peiretti F, Mueller C, Kopp F, Alessi MC, Cozzone PJ, Nalbone G, Bernard M. MRI follow-up of TNFdependent differential progression of atherosclerotic wallthickening in mouse aortic arch from early to advanced stages. Atherosclerosis . 2007;195:e93-99. https://doi.org/10.1016/j.atherosclerosis.2007.06.015
  19. Ohta H, Wada H, Niwa T, Kirii H, Iwamoto N, Fujii H, Saito K, Sekikawa K, Seishima M. Disruption of tumor necrosis factoralpha gene diminishes the development of atherosclerosis in ApoEdeficient mice. Atherosclerosis. 2005;180:11-17. https://doi.org/10.1016/j.atherosclerosis.2004.11.016
  20. Yun SJ, Ha JM, Kim EK, Kim YW, Jin SY, Lee DH, Song SH, Kim CD, Shin HK, Bae SS. Akt1 isoform modulates phenotypic conversion of vascular smooth muscle cells. Biochim Biophys Acta. 2014;1842:2184-2192. https://doi.org/10.1016/j.bbadis.2014.08.014
  21. Ha JM, Yun SJ, Kim YW, Jin SY, Lee HS, Song SH, Shin HK, Bae SS. Platelet-derived growth factor regulates vascular smooth muscle phenotype via mammalian target of rapamycin complex 1. Biochem Biophys Res Commun. 2015;464:57-62. https://doi.org/10.1016/j.bbrc.2015.05.097
  22. Kim SH, Yun SJ, Kim YH, Ha JM, Jin SY, Lee HS, Kim SJ, Shin HK, Chung SW, Bae SS. Essential role of kruppel-like factor 5 during tumor necrosis factor ${\alpha}$-induced phenotypic conversion of vascular smooth muscle cells. Biochem Biophys Res Commun. 2015;463:1323-1327. https://doi.org/10.1016/j.bbrc.2015.06.123
  23. Hayashi K, Shibata K, Morita T, Iwasaki K, Watanabe M, Sobue K. Insulin receptor substrate-1/SHP-2 interaction, a phenotypedependent switching machinery of insulin-like growth factor-I signaling in vascular smooth muscle cells. J Biol Chem. 2004;279: 40807-40818. https://doi.org/10.1074/jbc.M405100200
  24. Wang CC, Gurevich I, Draznin B. Insulin affects vascular smooth muscle cell phenotype and migration via distinct signaling pathways. Diabetes. 2003;52:2562-25629. https://doi.org/10.2337/diabetes.52.10.2562
  25. van Vliet J, Turner J, Crossley M. Human Kruppel-like factor 8: a CACCC-box binding protein that associates with CtBP and represses transcription. Nucleic Acids Res. 2000;28:1955-1962. https://doi.org/10.1093/nar/28.9.1955
  26. Gao D, Niu X, Ning N, Hao G. Regulation of angiotensin II-Induced Kruppel-like factor 5 expression in vascular smooth muscle cells. Biol Pharm Bull . 2006;29:2004-2008. https://doi.org/10.1248/bpb.29.2004
  27. Garvey SM, Sinden DS, Schoppee Bortz PD, Wamhoff BR. Cyclosporine up-regulates Kruppel-like factor-4 (KLF4) in vascular smooth muscle cells and drives phenotypic modulation in vivo. J Pharmacol Exp Ther. 2010;333:34-42. https://doi.org/10.1124/jpet.109.163949
  28. Liu Y, Sinha S, McDonald OG, Shang Y, Hoofnagle MH, Owens GK. Kruppel-like factor 4 abrogates myocardin-induced activation of smooth muscle gene expression. J Biol Chem. 2005;280:9719-9727. https://doi.org/10.1074/jbc.M412862200
  29. Nagai R, Suzuki T, Aizawa K, Shindo T, Manabe I. Significance of the transcription factor KLF5 in cardiovascular remodeling. J Thromb Haemost. 2005;3:1569-1576. https://doi.org/10.1111/j.1538-7836.2005.01366.x
  30. Yoshida T, Kaestner KH, Owens GK. Conditional deletion of Kruppel-like factor 4 delays downregulation of smooth muscle cell differentiation markers but accelerates neointimal formation following vascular injury. Circ Res. 2008;102:1548-1557. https://doi.org/10.1161/CIRCRESAHA.108.176974
  31. Wang D, Chang PS, Wang Z, Sutherland L, Richardson JA, Small E, Krieg PA, Olson EN. Activation of cardiac gene expression by myocardin, a transcriptional cofactor for serum response factor. Cell . 2001;105:851-862. https://doi.org/10.1016/S0092-8674(01)00404-4
  32. Yoshida T, Sinha S, Dandre F, Wamhoff BR, Hoofnagle MH, Kremer BE, Wang DZ, Olson EN, Owens GK. Myocardin is a key regulator of CArG-dependent transcription of multiple smooth muscle marker genes. Circ Res. 2003;92:856-864. https://doi.org/10.1161/01.RES.0000068405.49081.09
  33. Li HX, Han M, Bernier M, Zheng B, Sun SG, Su M, Zhang R, Fu JR, Wen JK. Kruppel-like factor 4 promotes differentiation by transforming growth factor-beta receptor-mediated Smad and p38 MAPK signaling in vascular smooth muscle cells. J Biol Chem. 2010;285:17846-17856. https://doi.org/10.1074/jbc.M109.076992
  34. Agarwal A, Das K, Lerner N, Sathe S, Cicek M, Casey G, Sizemore N. The AKT/I kappa B kinase pathway promotes angiogenic/metastatic gene expression in colorectal cancer by activating nuclear factorkappa B and beta-catenin. Oncogene. 2005;24:1021-1031. https://doi.org/10.1038/sj.onc.1208296
  35. Mansell A, Khelef N, Cossart P, O'Neill LA. Internalin B activates nuclear factor-kappa B via Ras, phosphoinositide 3-kinase, and Akt. J Biol Chem. 2001;276:43597-43603. https://doi.org/10.1074/jbc.M105202200
  36. Yang CH, Murti A, Pfeffer SR, Kim JG, Donner DB, Pfeffer LM. Interferon alpha /beta promotes cell survival by activating nuclear factor kappa B through phosphatidylinositol 3-kinase and Akt. J Biol Chem. 2001;276:13756-13761. https://doi.org/10.1074/jbc.M011006200
  37. Wang X, Urvalek AM, Liu J, Zhao J. Activation of KLF8 transcription by focal adhesion kinase in human ovarian epithelial and cancer cells. J Biol Chem. 2008;283:13934-13942. https://doi.org/10.1074/jbc.M709300200
  38. Suzuki T, Sawaki D, Aizawa K, Munemasa Y, Matsumura T, Ishida J, Nagai R. Kruppel-like factor 5 shows proliferation-specific roles in vascular remodeling, direct stimulation of cell growth, and inhibition of apoptosis. J Biol Chem. 2009;284:9549-9557. https://doi.org/10.1074/jbc.M806230200
  39. Bafford R, Sui XX, Wang G, Conte M. Angiotensin II and tumor necrosis factor-alpha upregulate survivin and Kruppel-like factor 5 in smooth muscle cells: Potential relevance to vein graft hyperplasia. Surgery. 2006;140:289-296. https://doi.org/10.1016/j.surg.2006.04.004
  40. Hoshino Y, Kurabayashi M, Kanda T, Hasegawa A, Sakamoto H, Okamoto E, Kowase K, Watanabe N, Manabe I, Suzuki T, Nakano A, Takase S, Wilcox JN, Nagai R. Regulated expression of the BTEB2 transcription factor in vascular smooth muscle cells: analysis of developmental and pathological expression profiles shows implications as a predictive factor for restenosis. Circulation. 2000;102:2528-2554. https://doi.org/10.1161/01.CIR.102.20.2528
  41. Ogata T, Kurabayashi M, Hoshino Y, Ishikawa S, Takeyoshi I, Morishita Y, Nagai R. Inducible expression of BTEB2, a member of the zinc-finger family of transcription factors, in cardiac allograft arteriosclerosis. Transplant Proc. 2000;32:2032-2033. https://doi.org/10.1016/S0041-1345(00)01544-X

피인용 문헌

  1. Smooth muscle cell differentiation: Mechanisms and models for vascular diseases vol.12, pp.6, 2017, https://doi.org/10.1007/s11515-017-1473-z
  2. Comparative Studies of Fibrin-Based Engineered Vascular Tissues and Notch Signaling from Progenitor Cells vol.6, pp.5, 2017, https://doi.org/10.1021/acsbiomaterials.0c00255