Skip to main content
Log in

Angiotensin-converting enzyme signalling in human preadipocytes and adipocytes

  • Research Article
  • Published:
Central European Journal of Biology

Abstract

Angiotensin-converting enzyme (ACE, kininase II) is a plasma membrane zinc metallopeptidase that acts as a key enzyme for the extracellular conversion of vasoactive peptides. Recently, ACE outside-in signalling in endothelial cells has been described. The present study tested the hypothesis that ACE signalling is not restricted to endothelial cells and may act as an additional peptide receptor on human preadipocytes and adipocytes. ACE protein levels were not changed during adipose conversion of human primary preadipocytes. The enzyme was primarily localized to the non-detergent-resistant fraction of the membrane and phosphorylated in non-dividing cells. Antibody arrays of whole cell lysate detected putative ACE-interacting proteins, which all share important roles in cell cycle control and/or apoptosis. These findings suggest that ACE is a versatile molecule, involved both in the regulation of extracellular peptide concentrations and direct intracellular signalling. In human adipose cells ACE may potentially influence exit from the cell cycle, differentiation, and programmed cell death signalling.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. L. Pénicaud, B. Cousin, C. Leloup, A. Lorsignol and L. Casteilla: “The autonomic nervous system, adipose tissue plasticity, and energy balance”, Nutrition, Vol. 16, (2000), pp. 903–908.

    Article  PubMed  Google Scholar 

  2. A. Sorisky, R. Magun and A.M. Gagnon: “Adipose cell apoptosis: death in the energy depot”, Int. J. Obesity, Vol. 24,Suppl. 4, (2000), pp. S3–S7.

    CAS  Google Scholar 

  3. M.A. Della-Fera and C.A. Baile: “Roles for melanocortins and leptin in adipose tissue apoptosis and fat deposition”, Peptides, Vol. 26, (2005), pp. 1782–1787.

    Article  PubMed  CAS  Google Scholar 

  4. R.A. Hegele: “Phenomics, lipodystrophy, and the metabolic syndrome”, Trends Cardiovas. Med., Vol. 4, (2004), pp. 133–137.

    Article  CAS  Google Scholar 

  5. P. Schling and G. Löffler: “Cross talk between adipose tissue cells: impact on pathophysiology”, News Physiol. Sci., Vol. 17, (2002), pp. 99–104.

    PubMed  CAS  Google Scholar 

  6. S. Engeli, P. Schling, K. Gorzelniak, M. Boschmann, J. Janke, G. Ailhaud, M. Teboul, F. Massiéra and A.M. Sharma: “The adipose-tissue renin-angiotensin-aldosterone system: role in the metabolic syndrome¿’, Int. J. Biochem. Cell B., Vol. 35, (2003), pp. 807–825.

    Article  CAS  Google Scholar 

  7. P. Schling: “Expression of angiotensin II receptors type 1 and type 2 in human preadipose cells during differentiation”, Horm. Metab. Res., Vol. 34, (2002), pp. 709–715.

    Article  PubMed  CAS  Google Scholar 

  8. H.L. Jackman, M.G. Massad, M. Sekosan, F. Tan, V. Brovkovych, B.M. Marcic and E.G. Erdos: “Angiotensin 1–9 and 1–7 release in human heart: role of cathepsin A”, Hypertension, Vol. 39, (2002), pp. 976–981.

    Article  PubMed  CAS  Google Scholar 

  9. R.A.S. Santos, M.J. Campagnole-Santos and S.P. Andrade: “Angiotensin-(1–7): an update”, Regul. Peptides, Vol. 91, (2000), pp. 45–62.

    Article  CAS  Google Scholar 

  10. W.S. Chen, M.K. Sim and M.L. Go: “Structure-activity and structure-binding studies of des-Asp(1)-angiotensin I analogues on the rabbit pulmonary artery”, Regul. Peptides, Vol. 106, (2002), pp. 39–46.

    Article  CAS  Google Scholar 

  11. A. Reaux, M.C. Fournie-Zaluski and C. Llorens-Cortes: “Angiotensin III: a central regulator of vasopressin release and blood pressure”, Trends Endocrin. Met., Vol. 12, (2001), pp. 157–162.

    Article  CAS  Google Scholar 

  12. O. von Bohlen and Halbach: “Angiotensin IV in the central nervous system”, Cell Tissue Res., Vol. 311, (2003), pp. 1–9.

    Article  CAS  Google Scholar 

  13. I. Fruitier-Arnaudin, M. Cohen, S. Bordenave, F. Sannier and J.M. Piot: “Comparative effects of angiotensin IV and two hemorphins on angiotensin-converting enzyme activity”, Peptides, Vol. 23, (2002), pp. 1465–1470.

    Article  PubMed  CAS  Google Scholar 

  14. E.G. Erdös, P.A. Deddish and B.M. Marcic: “Potentiation of Bradykinin Actions by ACE Inhibitors”, Trends Endocrin. Met., Vol. 10, (1999), pp. 223–229.

    Article  Google Scholar 

  15. T. Benzing, I. Fleming, A. Blaukat, W. Müller-Esterl and R. Busse: “Angiotensin-converting enzyme inhibitor ramiprilat interferes with the sequestration of the B2 kinin receptor within the plasma membrane of native endothelial cells”, Circulation, Vol. 99, (1999), pp. 2034–2040.

    PubMed  CAS  Google Scholar 

  16. B.M. Marcic and E.G.J. Erdös: “Protein kinase C and phosphatase inhibitors block the ability of angiotensin I-converting enzyme inhibitors to resensitize the receptor to bradykinin without altering the primary effects of bradykinin”, J. Pharmacol. Exp. Ther., Vol. 294, (2000), pp. 605–612.

    PubMed  CAS  Google Scholar 

  17. B.M. Marcic, P.A. Deddish, R.A. Skidgel, E.G. Erdös, R.D. Minshall and F. Tan: “Replacement of the transmembrane anchor in angiotensin I-converting enzyme (ACE) with a glycosylphosphatidylinositol tail affects activation of the B2 bradykinin receptor by ACE inhibitors”, J. Biol. Chem., Vol. 275, (2000), pp. 16110–16118.

    Article  PubMed  CAS  Google Scholar 

  18. K. Kohlstedt, F. Shoghi, W. Müller-Esterl, R. Busse and I. Flemming: “CK2 phosphorylates the angiotensin-converting enzyme and regulates its retention in the endothelial cell plasma membrane”, Circ. Res., Vol. 91, (2002), pp. 749–756.

    Article  PubMed  CAS  Google Scholar 

  19. K. Kohlstedt, R.P. Brandes, W. Müller-Esterl, R. Busse and I. Flemming: “Angiotensin-converting enzyme is involved in outside-in signaling in endothelial cells”, Circ. Res., Vol. 94, (2004), pp. 60–97.

    Article  PubMed  CAS  Google Scholar 

  20. K. Kohlstedt, R. Busse and I. Fleming: “Signaling via the angiotensin-converting enzyme enhances the expression of cyclooxygenase-2 in endothelial cells”, Hypertension, Vol. 45, (2005), pp. 126–132.

    PubMed  CAS  Google Scholar 

  21. K. Kohlstedt, R. Kellner, R. Busse and I. Fleming: “Signaling via the angiotensin-converting enzyme results in the phosphorylation of the nonmuscle myosin heavy chain IIA”, Mol. Pharmacol., Vol. 69, (2006), pp. 19–26.

    Article  PubMed  CAS  Google Scholar 

  22. K. Kohlstedt, C. Gershome, M. Friedrich, W. Muller-Esterl, F. Alhenc-Gelas, R. Busse and I. Fleming: “Angiotensin converting enzyme (ACE) dimerization is the initial step in the ACE inhibitor-induced ACE signaling cascade in endothelial cells”, Mol. Pharmacol., (2006), e-pub. ahead of print.

  23. P. Schling, H. Mallow, A. Trindl and G. Löffler: “Evidence for a local renin angiotensin system in primary cultured human preadipocytes”, Int. J. Obesity, Vol. 23, (1999), pp. 336–341.

    Article  CAS  Google Scholar 

  24. P. Schling and G. Löffler: “Effects of angiotensin II on adipose conversion and expression of genes of the renin-angiotensin system in human preadipocytes”, Horm. Metab. Res., Vol. 33, (2001), pp. 189–195.

    Article  PubMed  CAS  Google Scholar 

  25. P.K. Smith, R.I. Krohn, G.T. Hermanson, A.K. Mallia, F.H. Gartner, M.D. Provenzano, E.K. Fujimoto, N.M. Goeke, B.J. Olson and D.C. Klenk: “Measurement of protein using bicinchoninic acid”, Anal. Biochem., Vol. 150, (1985), pp. 76–85.

    Article  PubMed  CAS  Google Scholar 

  26. D. Wessel and U.I. Flügge: “A method for the quantitative recovery of protein in dilute solution in the presence of detergents and lipids”, Anal. Biochem., Vol. 138, (1984), pp. 141–143.

    Article  PubMed  CAS  Google Scholar 

  27. A.M. Brunati, A. Donella-Deana, P. James, M. Quadroni, A. Contri, O. Martin and L.A. Pinna: “Molecular features underlying the sequential phosphorylation of HS1 protein and its association with c-Fgr protein-tyrosine kinase”, J. Biol. Chem., Vol. 274, (1999), pp. 7557–7564.

    Article  PubMed  CAS  Google Scholar 

  28. J.P. Salles, M. Gayral-Taminh, J. Fauvel, I. Delobbe, M. Mignon-Conté, J.J. Conté and H. Chap: “Sustained effect of angiotensin II on tyrosine phosphorylation of annexin I in glomerular mesangial cells”, J. Biol. Chem., Vol. 268, (1993), pp. 12805–12811.

    PubMed  CAS  Google Scholar 

  29. D.L. Crandall, G. Gordon, H.E. Herzlinger, B.D. Saunders, R.C. Zolotor, P. Cervoni and J.G. Kral: “Transforming growth factor alpha and atrial natriuretic peptide in white adipose tissue depots in rats”, Eur. J. Clin. Invest., Vol. 22, (1992), pp. 676–680.

    Article  PubMed  CAS  Google Scholar 

  30. J. Antras, F. Hilliou, G. Redziniak and J. Pairault: “Decreased biosynthesis of actin and cellular fibronectin during adipose conversion of 3T3-F442A cells. Reorganization of the cytoarchitecture and extracellular matrix fibronectin”, Biol. Cell, Vol. 66, (1989), pp. 247–254.

    Article  PubMed  CAS  Google Scholar 

  31. K. Simons and D. Toomre: “Lipid rafts and signal transduction”, Nat. Rev. Mol. Cell Bio., Vol. 1, (2000), pp. 31–41.

    Article  CAS  Google Scholar 

  32. W. Drobnik, H. Borsukova, A. Böttcher, A. Pfeiffer, G. Liebisch, G.J. Schutz, H. Schindler and G. Schmitz: “Apo AI/ABCA1-dependent and HDL3-mediated lipid efflux from compositionally distinct cholesterol-based microdomains’, Traffic, Vol. 3, (2002), pp. 268–278.

    Article  PubMed  Google Scholar 

  33. A.J. Mendez, G. Lin, D.P. Wade, R.M. Lawn and J.F. Oram: “Membrane lipid domains distinct from cholesterol/sphingomyelin-rich rafts are involved in the ABCA1-mediated lipid secretory pathway”, J. Biol. Chem., Vol. 276, (2001), pp. 3158–3166.

    Article  PubMed  CAS  Google Scholar 

  34. J. Arribas, L. Coodly, P. Vollmer, T.K. Kishimoto, S. Rose-John and J. Massagué: “Diverse cell surface protein ectodomains are shed by a system sensitive to metallo-protease inhibitors”, J. Biol. Chem., Vol. 271, (1996), pp. 11376–11382.

    Article  PubMed  CAS  Google Scholar 

  35. U. Wang, T.R. Wu, S. Cai, T. Welte and Y.E. Chin: “Stat1 as a component of tumor necrosis factor alpha receptor 1-TRADD signaling complex to inhibit NF-kappaB activation”, Mol. Cell. Biol., Vol. 20, (2000), pp. 4504–4512.

    Google Scholar 

  36. P.R.B. Caldwell, B.C. Seegal, K.C. Hsu, M. Das and R.L. Soffer: “Angiotensinconverting enzyme: vascular endothelial localization”, Science, Vol. 191, (1976), pp. 1050–1051.

    PubMed  CAS  Google Scholar 

  37. J.R. Jonsson, P.A. Game, R.J. Head and D.B. Frewin: “The expression and localisation of the angiotensin-converting enzyme mRNA in human adipose tissue”, Blood Pressure, Vol. 3, (1994), pp. 72–75.

    PubMed  CAS  Google Scholar 

  38. R.O. Zandomeni: “Kinetics of inhibition by 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole on calf thymus casein kinase II”, Biochem. J., Vol. 262, (1989), pp. 469–473.

    PubMed  CAS  Google Scholar 

  39. W. Henning and H.-W. Stürzbecher: “Homologous recombination and cell cycle checkpoints: Rad51 in tumour progression and therapy resistance”, Toxicology, Vol. 193, (2003), pp. 91–109.

    Article  PubMed  CAS  Google Scholar 

  40. Y. Huang, S. Nakada, T. Ishiko, T. Utsugisawa, R. Datta, S. Kharbanda, K. Yoshida, R.V. Talanian, R. Weichselbaum, D. Kufe and Z.M. Yuan: “Role for caspasemediated cleavage of Rad51 in induction of apoptosis by DNA damage”, Mol. Cell. Biol., Vol. 19, (1999), pp. 2986–2997.

    PubMed  CAS  Google Scholar 

  41. L.A. Bannister and J.C. Schimenti: “Homologous recombinational repair proteins in mouse meiosis”, Cytogenet. Genome Res., Vol. 107, (2004), pp. 191–200.

    Article  PubMed  CAS  Google Scholar 

  42. J.J. Sironi and T. Ouchi: “STAT1-induced apoptosis is mediated by caspases 2, 3 and 7”, J. Biol. Chem., Vol. 279, (2004), pp. 4066–4074.

    Article  PubMed  CAS  Google Scholar 

  43. M. Castedo, J.-L. Perfetti, T. Roumier and G. Kroemer: “Cyclin-dependent kinase-1: linking apoptosis to cell cycle and mitotic catastrophe”, Cell Death Differ., Vol. 9, (2002), pp. 1287–1293.

    Article  PubMed  CAS  Google Scholar 

  44. H.-Y. Wang and C.C. Malbon: “G(s)alpha repression of adipogenesis via Syk”, J. Biol. Chem., Vol. 274, (1999), pp. 32159–32166.

    Article  PubMed  CAS  Google Scholar 

  45. Y. Takada and B.B. Aggerwal: “TNF activates Syk protein tyrosine kinase leading to TNF-induced MAPK activation, NF-kappaB activation, and apoptosis”, J. Immunol., Vol. 173, (2004), pp. 1066–1077.

    PubMed  CAS  Google Scholar 

  46. G. Chakraborty, H. Rangaswami, S. Jain and G.C. Kundu: “Hypoxia Regulates Crosstalk between Syk and Lck leading to Breast Cancer Progresion and Angiogenesis”, J. Biol. Chem., (2006), in press.

  47. C. Belka, C. Gruber, V. Jendrossek, S. Wesselborg and W. Budach: “The tyrosine kinase Lck is involved in regulation of mitochondrial apoptosis pathways”, Oncogene, Vol. 22, (2003), pp. 176–185.

    Article  PubMed  CAS  Google Scholar 

  48. A.K. Samraj, C. Stroh, U. Fischer and K. Schulze-Osthoff: “The tyrosine kinase Lck is a positive regulator of the mitochondrial apoptosis pathway by controlling Bak expression”, Oncogene, Vol. 25, (2006), pp. 186–197.

    PubMed  CAS  Google Scholar 

  49. A.M. Brunati, A. Donella-Deana, P. James, M. Quadroni, A. Contri, O. Marin and L.A. Pinna: “Molecular features underlying the sequential phosphorylation of HS1 protein and its association with c-Fgr protein-tyrosine kinase”, J. Biol. Chem., Vol. 274, (1999), pp. 7557–7564.

    Article  PubMed  CAS  Google Scholar 

  50. K. Katagiri, K.K. Yokoyama, T. Yamamoto, S. Omura, S. Irie and T. Katagiri: “Lyn and Fgr protein-tyrosine kinases prevent apoptosis during retinoic acid-induced granulocytic differentiation of HL-60 cells”, J. Biol. Chem., Vol. 271, (1996), pp. 11557–11562.

    Article  PubMed  CAS  Google Scholar 

  51. C.M. Vines, J.W. Potter, Y. Xu, R.L. Geahlen, P.S. Costello, V.L. Tybulewicz, C.A. Lowell, P.W. Chang, H.D. Gresham and C.L. Willam: “Inhibition of beta 2 integrin receptor and Syk kinase signaling in monocytes by the Src family kinase Fgr”, Immunity, Vol. 15, (2001), pp. 507–519.

    Article  PubMed  CAS  Google Scholar 

  52. F. Tsuruta, J. Sunayama, Y. Mori, S. Hattori, S. Shiizu, Y. Tsujimoto, K. Yoshioka, N. Masuyama and Y. Gotoh: “JNK promotes Bax translocation to mitochondria through phosphorylation of 14-3-3 proteins”, EMBO J., Vol. 23, (2004), pp. 1889–1899.

    Article  PubMed  CAS  Google Scholar 

  53. J. Hitomi, T. Katayama, Y. Eguchi, T. Kudo, M. Taniguchi, Y. Koyama, T. Manabe, S. Yamagishi, Y. Bando, K. Imaizumi, Y. Tsujimoto and M. Tohyama: “Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death,” J. Cell Biol., Vol. 165, (2004), pp. 347–356.

    Article  PubMed  CAS  Google Scholar 

  54. A.G. Porter and R.U. Jänicke: “Emerging roles of caspase-3 in apoptosis”, Cell Death Differ., Vol. 6, (1999), pp. 99–104.

    Article  PubMed  CAS  Google Scholar 

  55. Y. Imai, T. Kimura, A. Murakami, N. Yajima, K. Sakamaki and S. Yonehara: “The CED-4-homologous protein FLASH is involved in Fas-mediated activation of caspase-8 during apoptosis”, Nature, Vol. 398, (1999), pp. 777–785.

    Article  PubMed  CAS  Google Scholar 

  56. Y.-H. Choi, K.-B. Kim, H.-H. Kin, G.-S. Hong, Y.-K. Kwon, C.-W. Chung, Y.-M. Park, Z.-J. Shen, B.-J. Kim, S.-Y. Lee and Y.-K. Jung: ’FLASH coordinates NF-kappa B activity via TRAF2”, J. Biol. Chem., Vol. 276, (2001), pp. 25073–25077.

    Article  PubMed  CAS  Google Scholar 

  57. A. Stockinger, A. Eger, J. Wolf, H. Beug and R. Foisner: “E-cadherin regulates cell growth by modulating proliferation-dependent beta-catenin transcriptional activity”, J. Cell Biol., Vol. 154, (2001), pp. 1185–1196.

    Article  PubMed  CAS  Google Scholar 

  58. U. Steinhusen, J. Weiske, V. Badock, R. Tauber, K. Bommert and O. Huber: “Cleavage and shedding of E-cadherin after induction of apoptosis”, J. Biol. Chem., Vol. 276, (2001), pp. 4972–4980.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

About this article

Cite this article

Böttcher, A., Böttcher, A., Schmitz, G. et al. Angiotensin-converting enzyme signalling in human preadipocytes and adipocytes. cent.eur.j.biol. 1, 203–220 (2006). https://doi.org/10.2478/s11535-006-0015-5

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.2478/s11535-006-0015-5

Keywords

Navigation