Pflügers Archiv - European Journal of Physiology

, Volume 469, Issue 9, pp 1177–1188

Vasculo-protective effect of BMS-309403 is independent of its specific inhibition of fatty acid-binding protein 4

  • Yuta Okamura
  • Kosuke Otani
  • Akihiro Sekiguchi
  • Taisuke Kogane
  • Chiharu Kakuda
  • Yuzaburo Sakamoto
  • Tomoko Kodama
  • Muneyoshi Okada
  • Hideyuki Yamawaki
Signaling and cell physiology
Part of the following topical collections:
  1. Signaling and cell physiology

Abstract

Fatty acid-binding protein (FABP) 4 is an adipocytokine mainly expressed in adipocyte and macrophage. Blood FABP4 is related not only to metabolic disorders including insulin resistance and atherosclerosis but also increased blood pressure. We tested the hypothesis that FABP4 plays roles in pathogenesis of hypertension development including proliferation, migration, and inflammation of vascular smooth muscle cells (SMCs) as well as contractile reactivity. FABP4 alone had no influence on proliferation, migration, and inflammation of rat mesenteric arterial SMCs, while it significantly enhanced smooth muscle contraction and increases of systolic blood pressure (SBP) induced by noradrenaline (NA). BMS-309403, an FABP4 inhibitor, significantly inhibited platelet-derived growth factor-BB-induced DNA synthesis and migration via preventing p38 and HSP27 activation. Further, BMS-309403 significantly inhibited tumor necrosis factor-α-induced expression of vascular cell adhesion molecule-1 and monocyte chemotactic protein-1 as well as monocyte adhesion via preventing NF-κB activation. Interestingly, SMCs do not express FABP4. Long-term treatment of spontaneously hypertensive rats (SHR) with BMS-309403 significantly inhibited impaired relaxation in isolated mesenteric arteries and left ventricular hypertrophy, while it had no influence on SBP. We for the first time showed that FABP4 acutely enhances NA-induced increases of SBP possibly through the enhancement of peripheral arterial contractility. BMS-309403 prevents proliferation, migration, and inflammatory responses of SMCs, although exogenous application of FABP4 has no influence on the cellular responses. Furthermore, we demonstrated that long-term treatment with BMS-309403 partially improves the pathological conditions of SHR. These results indicate that BMS-309403 would be useful for developing a new pharmacotherapeutic agent against obesity-associated hypertension and complications.

Keywords

Adipocytokine Vascular smooth muscle Hypertension Contractility Inflammation Proliferation Migration 

Supplementary material

424_2017_1976_MOESM1_ESM.pdf (125 kb)
ESM 1(PDF 124 kb)

References

  1. 1.
    Aragones G, Saavedra P, Heras M, Cabre A, Girona J, Masana L (2012) Fatty acid-binding protein 4 impairs the insulin-dependent nitric oxide pathway in vascular endothelial cells. Cardiovasc Diabetol 11:72. doi:10.1186/1475-2840-11-72 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Astern JM, Pendergraft WF 3rd, Falk RJ, Jennette JC, Schmaier AH, Mahdi F, Preston GA (2007) Myeloperoxidase interacts with endothelial cell-surface cytokeratin 1 and modulates bradykinin production by the plasma Kallikrein-Kinin system. Am J Pathol 171:349–360. doi:10.2353/ajpath.2007.060831 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Azzazy HM, Pelsers MM, Christenson RH (2006) Unbound free fatty acids and heart-type fatty acid-binding protein: diagnostic assays and clinical applications. Clin Chem 52:19–29. doi:10.1373/clinchem.2005.056143 CrossRefPubMedGoogle Scholar
  4. 4.
    Bhushan B, Khalyfa A, Spruyt K, Kheirandish-Gozal L, Capdevila OS, Bhattacharjee R, Kim J, Keating B, Hakonarson H, Gozal D (2011) Fatty-acid binding protein 4 gene polymorphisms and plasma levels in children with obstructive sleep apnea. Sleep Med 12:666–671. doi:10.1016/j.sleep.2010.12.014 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Boss M, Kemmerer M, Brune B, Namgaladze D (2015) FABP4 inhibition suppresses PPARgamma activity and VLDL-induced foam cell formation in IL-4-polarized human macrophages. Atherosclerosis 240:424–430. doi:10.1016/j.atherosclerosis.2015.03.042 CrossRefPubMedGoogle Scholar
  6. 6.
    Cabre A, Lazaro I, Cofan M, Jarauta E, Plana N, Garcia-Otin AL, Ascaso JF, Ferre R, Civeira F, Ros E, Masana L (2010) FABP4 plasma levels are increased in familial combined hyperlipidemia. J Lipid Res 51:1173–1178. doi:10.1194/jlr.M900066 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Chan CK, Zhao Y, Liao SY, Zhang YL, Lee MY, Xu A, Tse HF, Vanhoutte PM (2013) A-FABP and oxidative stress underlie the impairment of endothelium-dependent relaxations to serotonin and the intima-medial thickening in the porcine coronary artery with regenerated endothelium. ACS Chem Neurosci 4:122–129. doi:10.1021/cn3000873 CrossRefPubMedGoogle Scholar
  8. 8.
    Choi OB, Park JH, Lee YJ, Lee CK, Won KJ, Kim J, Lee HM, Kim B (2009) Olibanum extract inhibits vascular smooth muscle cell migration and proliferation in response to platelet-derived growth factor. Korean J Physiol Pharmacol 13:107–113. doi:10.4196/kjpp.2009.13.2.107 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Distel RJ, Robinson GS, Spiegelman BM (1992) Fatty acid regulation of gene expression. Transcriptional and post-transcriptional mechanisms. J Biol Chem 267:5937–5941PubMedGoogle Scholar
  10. 10.
    Furuhashi M, Tuncman G, Gorgun CZ, Makowski L, Atsumi G, Vaillancourt E, Kono K, Babaev VR, Fazio S, Linton MF, Sulsky R, Robl JA, Parker RA, Hotamisligil GS (2007) Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2. Nature 447:959–965. doi:10.1038/nature05844 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Gan J, Li P, Wang Z, Chen J, Liang X, Liu M, Xie W, Yin R, Huang F (2013) Rosuvastatin suppresses platelet-derived growth factor-BB-induced vascular smooth muscle cell proliferation and migration via the MAPK signaling pathway. Exp Ther Med 6:899–903. doi:10.3892/etm.2013.1265 PubMedPubMedCentralGoogle Scholar
  12. 12.
    Garin-Shkolnik T, Rudich A, Hotamisligil GS, Rubinstein M (2014) FABP4 attenuates PPARgamma and adipogenesis and is inversely correlated with PPARgamma in adipose tissues. Diabetes 63:900–911. doi:10.2337/db13-0436 CrossRefPubMedGoogle Scholar
  13. 13.
    Girona J, Rosales R, Plana N, Saavedra P, Masana L, Vallve JC (2013) FABP4 induces vascular smooth muscle cell proliferation and migration through a MAPK-dependent pathway. PLoS One 8:e81914. doi:10.1371/journal.pone.0081914 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Hasan AA, Zisman T, Schmaier AH (1998) Identification of cytokeratin 1 as a binding protein and presentation receptor for kininogens on endothelial cells. Proc Natl Acad Sci U S A 95:3615–3620CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Hertzel AV, Bernlohr DA (2000) The mammalian fatty acid-binding protein multigene family: molecular and genetic insights into function. Trends Endocrinol Metab 11:175–180CrossRefPubMedGoogle Scholar
  16. 16.
    Hertzel AV, Hellberg K, Reynolds JM, Kruse AC, Juhlmann BE, Smith AJ, Sanders MA, Ohlendorf DH, Suttles J, Bernlohr DA (2009) Identification and characterization of a small molecule inhibitor of fatty acid binding proteins. J Med Chem 52:6024–6031. doi:10.1021/jm900720m CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Hotamisligil GS, Johnson RS, Distel RJ, Ellis R, Papaioannou VE, Spiegelman BM (1996) Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein. Science 274:1377–1379CrossRefPubMedGoogle Scholar
  18. 18.
    Hunt CR, Ro JH, Dobson DE, Min HY, Spiegelman BM (1986) Adipocyte P2 gene: developmental expression and homology of 5′-flanking sequences among fat cell-specific genes. Proc Natl Acad Sci U S A 83:3786–3790CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Kamijo A, Sugaya T, Hikawa A, Yamanouchi M, Hirata Y, Ishimitsu T, Numabe A, Takagi M, Hayakawa H, Tabei F, Sugimoto T, Mise N, Omata M, Kimura K (2006) Urinary liver-type fatty acid binding protein as a useful biomarker in chronic kidney disease. Mol Cell Biochem 284:175–182. doi:10.1007/s11010-005-9047-9 CrossRefPubMedGoogle Scholar
  20. 20.
    Kazama K, Usui T, Okada M, Hara Y, Yamawaki H (2012) Omentin plays an anti-inflammatory role through inhibition of TNF-alpha-induced superoxide production in vascular smooth muscle cells. Eur J Pharmacol 686:116–123. doi:10.1016/j.ejphar.2012.04.033 CrossRefPubMedGoogle Scholar
  21. 21.
    Kazama K, Okada M, Hara Y, Yamawaki H (2013) A novel adipocytokine, omentin, inhibits agonists-induced increases of blood pressure in rats. J Vet Med Sci 75:1029–1034CrossRefPubMedGoogle Scholar
  22. 22.
    Kleine AH, Glatz JF, Van Nieuwenhoven FA, Van der Vusse GJ (1992) Release of heart fatty acid-binding protein into plasma after acute myocardial infarction in man. Mol Cell Biochem 116:155–162CrossRefPubMedGoogle Scholar
  23. 23.
    Kubo T (1998) Cholinergic mechanism and blood pressure regulation in the central nervous system. Brain Res Bull 46: 475–481. doi:10.1016/S0361-9230(98)00041-0
  24. 24.
    Kunimoto H, Kazama K, Takai M, Oda M, Okada M, Yamawaki H (2015) Chemerin promotes the proliferation and migration of vascular smooth muscle and increases mouse blood pressure. Am J Physiol Heart Circ Physiol 309:H1017–H1028. doi:10.1152/ajpheart.00820.2014 PubMedGoogle Scholar
  25. 25.
    Lee MY, Li H, Xiao Y, Zhou Z, Xu A, Vanhoutte PM (2011) Chronic administration of BMS309403 improves endothelial function in apolipoprotein E-deficient mice and in cultured human endothelial cells. Br J Pharmacol 162:1564–1576. doi:10.1111/j.1476-5381.2010.01158.x CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Machida THT, Onoguchi A, Iizuka K, Hirafuji M (2014) Comparison of fatty acid-binding protein expression in vascular smooth muscle cells from stroke-prone spontaneously hypertensive and Wistar Kyoto rats. Pharmacologia 5:12–18. doi:10.5567/pharmacologia.2014.12.18 CrossRefGoogle Scholar
  27. 27.
    Maeda K, Cao H, Kono K, Gorgun CZ, Furuhashi M, Uysal KT, Cao Q, Atsumi G, Malone H, Krishnan B, Minokoshi Y, Kahn BB, Parker RA, Hotamisligil GS (2005) Adipocyte/macrophage fatty acid binding proteins control integrated metabolic responses in obesity and diabetes. Cell Metab 1:107–119. doi:10.1016/j.cmet.2004.12.008 CrossRefPubMedGoogle Scholar
  28. 28.
    Makowski L, Boord JB, Maeda K, Babaev VR, Uysal KT, Morgan MA, Parker RA, Suttles J, Fazio S, Hotamisligil GS, Linton MF (2001) Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis. Nat Med 7:699–705. doi:10.1038/89076 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Melki SA, Abumrad NA (1993) Expression of the adipocyte fatty acid-binding protein in streptozotocin-diabetes: effects of insulin deficiency and supplementation. J Lipid Res 34:1527–1534PubMedGoogle Scholar
  30. 30.
    Morita T, Okada M, Hara Y, Yamawaki H (2011) Mechanisms underlying impairment of endothelium-dependent relaxation by fetal bovine serum in organ-cultured rat mesenteric artery. Eur J Pharmacol 668:401–406. doi:10.1016/j.ejphar.2011.07.040 CrossRefPubMedGoogle Scholar
  31. 31.
    Ockner RK, Manning JA, Poppenhausen RB, Ho WK (1972) A binding protein for fatty acids in cytosol of intestinal mucosa, liver, myocardium, and other tissues. Science 177:56–58CrossRefPubMedGoogle Scholar
  32. 32.
    Ota H, Furuhashi M, Ishimura S, Koyama M, Okazaki Y, Mita T, Fuseya T, Yamashita T, Tanaka M, Yoshida H, Shimamoto K, Miura T (2012) Elevation of fatty acid-binding protein 4 is predisposed by family history of hypertension and contributes to blood pressure elevation. Am J Hypertens 25:1124–1130. doi:10.1038/ajh.2012.88 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Otani K, Okada M, Yamawaki H (2015) Expression pattern and function of tyrosine receptor kinase B isoforms in rat mesenteric arterial smooth muscle cells. Biochem Biophys Res Commun 467:683–689. doi:10.1016/j.bbrc.2015.10.084 CrossRefPubMedGoogle Scholar
  34. 34.
    Phalitakul S, Okada M, Hara Y, Yamawaki H (2012) A novel adipocytokine, vaspin inhibits platelet-derived growth factor-BB-induced migration of vascular smooth muscle cells. Biochem Biophys Res Commun 423:844–849. doi:10.1016/j.bbrc.2012.06.052 CrossRefPubMedGoogle Scholar
  35. 35.
    Pichon S, Bryckaert M, Berrou E (2004) Control of actin dynamics by p38 MAP kinase—Hsp27 distribution in the lamellipodium of smooth muscle cells. J Cell Sci 117:2569–2577. doi:10.1242/jcs.01110 CrossRefPubMedGoogle Scholar
  36. 36.
    Saavedra P, Girona J, Bosquet A, Guaita S, Canela N, Aragones G, Heras M, Masana L (2015) New insights into circulating FABP4: interaction with cytokeratin 1 on endothelial cell membranes. Biochim Biophys Acta 1853:2966–2974. doi:10.1016/j.bbamcr.2015.09.002 CrossRefPubMedGoogle Scholar
  37. 37.
    Sulsky R, Magnin DR, Huang Y, Simpkins L, Taunk P, Patel M, Zhu Y, Stouch TR, Bassolino-Klimas D, Parker R, Harrity T, Stoffel R, Taylor DS, Lavoie TB, Kish K, Jacobson BL, Sheriff S, Adam LP, Ewing WR, Robl JA (2007) Potent and selective biphenyl azole inhibitors of adipocyte fatty acid binding protein (aFABP). Bioorg Med Chem Lett 17:3511–3515. doi:10.1016/j.bmcl.2006.12.044 CrossRefPubMedGoogle Scholar
  38. 38.
    Terra X, Quintero Y, Auguet T, Porras JA, Hernandez M, Sabench F, Aguilar C, Luna AM, Del Castillo D, Richart C (2011) FABP 4 is associated with inflammatory markers and metabolic syndrome in morbidly obese women. Eur J Endocrinol 164:539–547. doi:10.1530/EJE-10-1195 CrossRefPubMedGoogle Scholar
  39. 39.
    Usui T, Okada M, Hara Y, Yamawaki H (2012) Death-associated protein kinase 3 mediates vascular inflammation and development of hypertension in spontaneously hypertensive rats. Hypertension 60:1031–1039. doi:10.1161/HYPERTENSIONAHA.112.200337 CrossRefPubMedGoogle Scholar
  40. 40.
    Usui T, Morita T, Okada M, Yamawaki H (2014) Histone deacetylase 4 controls neointimal hyperplasia via stimulating proliferation and migration of vascular smooth muscle cells. Hypertension 63:397–403. doi:10.1161/HYPERTENSIONAHA.113.01843 CrossRefPubMedGoogle Scholar
  41. 41.
    Uysal KT, Scheja L, Wiesbrock SM, Bonner-Weir S, Hotamisligil GS (2000) Improved glucose and lipid metabolism in genetically obese mice lacking aP2. Endocrinology 141:3388–3396. doi:10.1210/endo.141.9.7637 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Yuta Okamura
    • 1
  • Kosuke Otani
    • 1
  • Akihiro Sekiguchi
    • 1
  • Taisuke Kogane
    • 1
  • Chiharu Kakuda
    • 1
  • Yuzaburo Sakamoto
    • 1
  • Tomoko Kodama
    • 1
  • Muneyoshi Okada
    • 1
  • Hideyuki Yamawaki
    • 1
  1. 1.Laboratory of Veterinary Pharmacology, School of Veterinary MedicineKitasato UniversityAomoriJapan

Personalised recommendations