Skip to main content
SpringerLink
Log in

Effect of chronic endothelin blockade on PKC isoform distribution in mesenteric arteries from diabetic rats

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Hemodynamic changes, including increased vasoconstriction and reduced blood flow have been detected in both human diabetic patients and in animal models of diabetes. We previously demonstrated that the endothelin (ET) system was upregulated and involved in mediating the exaggerated vasoconstrictor responses in superior mesenteric artery (SMA) from diabetic rats. Chronic treatment of diabetic rats with the dual endothelin receptor antagonist, bosentan abolished the enhanced contractile responses in diabetic SMA. The biological actions of ET-1 have been shown to be coupled to the hydrolysis of phosphotidylinositol 4,5-biphosphate and phosphotidylcholine and the subsequent production of diacylglycerol (DAG). DAG is an activator of the classical and novel isoforms of PKC. Increases in PKC activity, associated with translocation of specific PKC isoforms from the cytosol to the membrane, have been implicated in the vasoconstrictor effect of ET-1. The goal of the present study was to determine whether chronic treatment of diabetic rats with bosentan influences the activation of specific PKC isoforms in SMA from diabetic rats. Elevated levels of PKCβ2 in both the cytosol and membrane fractions and PKCε in the membrane fraction were detected in SMA from diabetic rats. However, neither the levels nor the distribution between the cytosol and membrane fractions of any of these PKC isoforms were affected by the treatment of the diabetic rats with bosentan. These observations indicate that bosentan improves vascular reactivity in STZ-diabetic rats by mechanisms other than correction of increased activities of PKC isoforms. (Mol Cell Biochem xxx: 69–75, 2005)

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Takahashi K, Ghatei MA, Lam HC, O'Halloran DJ, Bloom SR: Elevated plasma endothelin in patients with diabetes mellitus. Diabetologia 33: 306–310, 1990

    Article  PubMed  CAS  Google Scholar 

  2. Collier A, Leach JP, McLellan A, Jardine A, Morton JJ, Small M: Plasma endothelinlike immunoreactivity levels in IDDM patients with microalbuminuria. Diabetes Care 15: 1038–1040, 1992

    PubMed  CAS  Google Scholar 

  3. Morabito E, Corsico N, Arrigoni Martelli E: Endothelins urinary excretion is increased in spontaneously diabetic rats: BB/BB. Life Sci 56: PL13–PL18, 1995

  4. Hopfner RL, Gopalakrishnan V: Endothelin: emerging role in diabetic vascular complications. Diabetologia 42: 1383–1394, 1999

    Article  PubMed  CAS  Google Scholar 

  5. Chakrabarti S, Chen S, Evans T, Karmazyn M: Endothelins in the microvasculature and heart in diabetes. Adv Exp Med Biol 498: 97–108, 2001

    PubMed  CAS  Google Scholar 

  6. Hopfner RL, Misurski D, Wilson TW, McNeill JR, Gopalakrishnan V: Insulin and vanadate restore decreased plasma endothelin concentrations and exaggerated vascular responses to normal in the streptozotocin diabetic rat. Diabetologia 41: 1233–1240, 1998

    Article  PubMed  CAS  Google Scholar 

  7. Murat N, Kalkan S, Gidener S: Effect of verapamil on responses to endothelin-1 in aortic rings from streptozotocin-induced diabetic rats. Pharmacol Res 40: 37–40, 1999

    Article  PubMed  CAS  Google Scholar 

  8. Mayhan WG, Irvine SD, Sharpe GM: Constrictor responses of resistance arterioles during diabetes mellitus. Diabetes Res Clin Pract 44: 147–156, 1999

    Article  PubMed  CAS  Google Scholar 

  9. Gilbert RE, Rumble JR, Cao Z, Cox AJ, van Eeden P, Allen TJ, Kelly DJ, Cooper ME: Endothelin receptor antagonism ameliorates mast cell infiltration, vascular hypertrophy, and epidermal growth factor expression in experimental diabetes. Circ Res 86: 158–165, 2000

    PubMed  CAS  Google Scholar 

  10. Takagi C, Bursell SE, Lin YW, Takagi H, Duh E, Jiang Z, Clermont AC, King GL: Regulation of retinal hemodynamics in diabetic rats by increased expression and action of endothelin-1. Invest Ophthalmol Vis Sci 37: 2504–2518, 1996

    PubMed  CAS  Google Scholar 

  11. Evans T, Deng DX, Chen S, Chakrabarti S: Endothelin receptor blockade prevents augmented extracellular matrix component mRNA expression and capillary basement membrane thickening in the retina of diabetic and galactose-fed rats. Diabetes 49: 662–666, 2000

    PubMed  CAS  Google Scholar 

  12. Verma S, Arikawa E, Lee S, Dumont AS, Yao L, McNeill JH: Exaggerated coronary reactivity to endothelin-1 in diabetes: reversal with bosentan. Can J Physiol Pharmacol 80: 980–986, 2002

    Article  PubMed  CAS  Google Scholar 

  13. Arikawa E, Verma S, Dumont AS, McNeill JH: Chronic bosentan treatment improves renal artery vascular function in diabetes. J Hypertens 19: 803–812, 2001

    Article  PubMed  CAS  Google Scholar 

  14. Arikkawa E, Cheung C, Swkirov I, McNeill JH: Effects of endothelin receptor blockade on hyper-vasoreactivity in streptozotocin-diabetic rats: vessel-specific involvement of thromboxane A2. Submitted, 2005

  15. Verma S, Arikawa E, McNeill JH: Long-term endothelin receptor blockade improves cardiovascular function in diabetes. Am J Hypertens 14: 679–687, 2001

    PubMed  CAS  Google Scholar 

  16. Douglas SA, Ohlstein EH: Signal transduction mechanisms mediating the vascular actions of endothelin. J Vasc Res 34: 152–164, 1997

    PubMed  CAS  Google Scholar 

  17. Auguet M, Delaflotte S, Chabrier PE, Braquet P: Comparative effects of endothelin and phorbol 12–13 dibutyrate in rat aorta. Life Sci 45: 2051–2059, 1989

    Article  PubMed  CAS  Google Scholar 

  18. Danthuluri NR, Brock TA: Endothelin receptor-coupling mechanisms in vascular smooth muscle: a role for protein kinase C. J Pharmacol Exp Ther 254: 393–399, 1990

    PubMed  CAS  Google Scholar 

  19. Ohlstein EH, Horohonich S, Hay DW: Cellular mechanisms of endothelin in rabbit aorta. J Pharmacol Exp Ther 250: 548–555, 1989

    PubMed  CAS  Google Scholar 

  20. Sugiura M, Inagami T, Hare GM, Johns JA: Endothelin action: inhibition by a protein kinase C inhibitor and involvement of phosphoinositols. Biochem Biophys Res Commun 158: 170–176, 1989

    Article  PubMed  CAS  Google Scholar 

  21. Tickerhoof MM, Farrell PA, Korzick DH: Alterations in rat coronary vasoreactivity and vascular protein kinase C isoforms in Type 1 diabetes. Am J Physiol Heart Circ Physiol 285: H2694–H2703, 2003

    PubMed  CAS  Google Scholar 

  22. Dempsey EC, Newton AC, Mochly-Rosen D, Fields AP, Reyland ME, Insel PA, Messing RO: Protein kinase C isozymes and the regulation of diverse cell responses. Am J Physiol Lung Cell Mol Physiol 279: L429–L438, 2000

    PubMed  CAS  Google Scholar 

  23. Idris I, Gray S, Donnelly R: Protein kinase C activation: isozyme-specific effects on metabolism and cardiovascular complications in diabetes. Diabetologia 44: 659–673, 2001

    Article  PubMed  CAS  Google Scholar 

  24. Way KJ, Katai N, King GL: Protein kinase C and the development of diabetic vascular complications. Diabet Med 18: 945–959, 2001

    Article  PubMed  CAS  Google Scholar 

  25. Park JY, Takahara N, Gabriele A, Chou E, Naruse K, Suzuma K, Yamauchi T, Ha SW, Meier M, Rhodes CJ, King GL: induction of endothelin-1 expression by glucose: An effect of protein kinase C activation. Diabetes 49: 1239–1248, 2000

    PubMed  CAS  Google Scholar 

  26. Kraft AS, Anderson WB: Phorbol esters increase the amount of Ca2+, phospholipid-dependent protein kinase associated with plasma membrane. Nature 301: 621–623, 1983

    Article  PubMed  CAS  Google Scholar 

  27. Jiang J, Ballinger CA, Wu Y, Dai Q, Cyr DM, Hohfeld J, Patterson C: CHIP is a U-box-dependent E3 ubiquitin ligase: identification of Hsc70 as a target for ubiquitylation. J Biol Chem 276: 42938–42944, 2001

    PubMed  CAS  Google Scholar 

  28. King GL, Brownlee M: The cellular and molecular mechanisms of diabetic complications. Endocrinol Metab Clin North Am 25: 255–270, 1996

    Article  PubMed  CAS  Google Scholar 

  29. Koya D, King GL: Protein kinase C activation and the development of diabetic complications. Diabetes 47: 859–866, 1998

    PubMed  CAS  Google Scholar 

  30. Inoguchi T, Battan R, Handler E, Sportsman JR, Heath W, King GL: Preferential elevation of protein kinase C isoform beta II and diacylglycerol levels in the aorta and heart of diabetic rats: differential reversibility to glycemic control by islet cell transplantation. Proc Natl Acad Sci USA 89: 11059–11063, 1992

    PubMed  CAS  Google Scholar 

  31. Haller H, Baur E, Quass P, Behrend M, Lindschau C, Distler A, Luft FC: High glucose concentrations and protein kinase C isoforms in vascular smooth muscle cells. Kidney Int 47: 1057–1067, 1995

    PubMed  CAS  Google Scholar 

  32. Christopher J, Velarde V, Zhang D, Mayfield D, Mayfield RK, Jaffa AA: Regulation of B(2)-kinin receptors by glucose in vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 280: H1537–H1546, 2001

    PubMed  CAS  Google Scholar 

  33. Ishii H, Koya D, King GL. Protein kinase C activation and its role in the development of vascular complications in diabetes mellitus. J Mol Med 76: 21–31, 1998

    Article  PubMed  CAS  Google Scholar 

  34. Abebe W, Harris KH, MacLeod KM: Enhanced contractile responses of arteries from diabetic rats to alpha 1-adrenoceptor stimulation in the absence and presence of extracellular calcium. J Cardiovasc Pharmacol 16: 239–248, 1990

    PubMed  CAS  Google Scholar 

  35. Abebe W, MacLeod KM: Influence of diabetes on norepinephrine-induced inositol 1,4,5-trisphosphate levels in rat aorta. Life Sci 49: PL85–PL90, 1991

    Article  PubMed  CAS  Google Scholar 

  36. Abebe W, Harris KH, MacLeod KM: Role of extracellular Ca2+ in the selective enhancement of contractile responses of arteries from diabetic rats to noradrenaline. Can J Physiol Pharmacol 72: 1544–1551, 1994

    PubMed  CAS  Google Scholar 

  37. Hattori Y, Kawasaki H, Kanno M, Fukao M: Enhanced 5-HT2 receptor mediated contractions in diabetic rat aorta: participation of Ca2+ channels associated with protein kinase C activity. J Vasc Res 32: 220–229, 1995

    Article  PubMed  CAS  Google Scholar 

  38. Jandeleit-Dahm K, Jackson B, Paxton D, Perich R, Johnston CI: Characterization of angiotensin converting enzyme from different rat vascular beds. Blood Press 4: 170–176, 1995

    PubMed  CAS  Google Scholar 

  39. Osicka TM, Yu Y, Lee V, Panagiotopoulos S, Kemp BE, Jerums G: Aminoguanidine and ramipril prevent diabetes-induced increases in protein kinase C activity in glomeruli, retina and mesenteric artery. Clin Sci (Lond) 100: 249–257, 2001

    CAS  Google Scholar 

  40. Nishizuka Y: Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 258: 607–614, 1992

    PubMed  CAS  Google Scholar 

  41. Benigni A, Colosio V, Brena C, Bruzzi I, Bertani T, Remuzzi G: Unselective inhibition of endothelin receptors reduces renal dysfunction in experimental diabetes. Diabetes 47: 450–456, 1998

    PubMed  CAS  Google Scholar 

  42. Deng D, Evans T, Mukherjee K, Downey D, Chakrabarti S: Diabetes-induced vascular dysfunction in the retina: role of endothelins. Diabetologia 42: 1228–1234, 1999

    Article  PubMed  CAS  Google Scholar 

  43. Gilbert RE, Rumble JR, Cao Z, Cox AJ, van Eeden P, Allen TJ, Kelly DJ, Cooper ME: Endothelin receptor antagonism ameliorates mast cell infiltration, vascular hypertrophy, and epidermal growth factor expression in experimental diabetes. Circ Res 86: 158–165, 2000

    PubMed  CAS  Google Scholar 

  44. Chen S, Evans T, Mukherjee K, Karmazyn M, Chakrabarti S: Diabetes-induced myocardial structural changes: role of endothelin-1 and its receptors. J Mol Cell Cardiol 32: 1621–1629, 2000

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada, V6T 1Z3

    Jihong Jiang, Lili Zhang, Kathleen M. MacLeod & John H. McNeill

  2. Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC, Canada, V6T 1Z3

    John H. McNeill

Authors
  1. Jihong Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lili Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kathleen M. MacLeod
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John H. McNeill
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John H. McNeill.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jiang, J., Zhang, L., MacLeod, K.M. et al. Effect of chronic endothelin blockade on PKC isoform distribution in mesenteric arteries from diabetic rats. Mol Cell Biochem 280, 69–75 (2005). https://doi.org/10.1007/s11010-005-8053-2

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-005-8053-2

Keyword

Search

Navigation