Skip to main content
SpringerLink
Log in

G-Proteins in Vascular Complications of Diabetes

  • Chapter
  • First Online:
Mechanisms of Vascular Defects in Diabetes Mellitus

Part of the book series: Advances in Biochemistry in Health and Disease ((ABHD,volume 17))

  • 1325 Accesses

Abstract

Vascular complications including impaired contractility and increased cell proliferation are the most common complications associated with diabetes, and chronic hyperglycemia appears to be an important contributing factor in this process. However, the precise mechanism(s) responsible for hyperglycemia-induced vascular dysfunction remains poorly characterized. Guanine nucleotide regulatory proteins (G-proteins) play a key role in the regulation of various signal transduction systems including adenylyl cyclase/cAMP and phospholipase C (PLC)/phosphatidyl inositol turnover (PI) which are implicated in the regulation of a variety of vascular functions including cell proliferation, hypertrophy, vascular tone and reactivity and the aberration of these pathways contribute to vascular complications in diabetes. The levels of inhibitory G-proteins (Giα-2 and Giα-3) are decreased in several tissues from streptozotocin diabetic rats and diabetic subjects. A relationship between the development of diabetes and Giα protein expression is also shown and suggests a role of decreased levels of Giα proteins in the pathogenesis of diabetes. In addition, exposure of aorta as well as VSMC with high glucose that simulate diabetic state also decreased the levels of Giα-2 and Giα-3 proteins. A correlation between the levels of glucose (in vivo and in vitro) and decreased expression of Giα proteins exists and suggests that hyperglycemia may be a contributing factor in diabetes-induced decreased expression of Giα proteins. The decreased levels of Giα proteins and associated adenylyl cyclase signaling in diabetes/hyperglycemia are attributed to the enhanced levels of vasoactive peptides. In addition, hyperglycemia-induced enhanced nitroxidative stress also contributes to the decreased expression of Giα proteins induced by high glucose. Furthermore, the basal adenylyl cyclase activity and cAMP levels are decreased in VSMC exposed to high glucose. On the other hand, Gqα proteins and the downstream molecules PKC and DAG are upregulated in different tissues from STZ-induced diabetic rats. In addition, VSMC exposed to high glucose also have enhanced expression of Gq/11α, PLCβ-1 and PLCβ-2 proteins. The enhanced levels of vasoactive peptides induced by hyperglycemia through oxidative stress, c-Src, growth factor receptor activation and MAP kinase signaling contribute to the enhanced expression of Gqα, PLCβ proteins in VSMC. The enhanced expression of Gqα and PLCβ has been shown to contribute to VSMC hypertrophy. It is thus suggested that the decreased levels of cAMP, Giα proteins and as well as overexpression of Gqα and PLCβ may be the contributing factors responsible for the vascular complications of diabetes/hyperglycemia. This review briefly summarizes some of the key studies on the modulation of G protein expression involving oxidative stress, growth factor receptor activation and associated signaling pathways in diabetes/hyperglycemia in VSMC and their potential role in the development of vascular complications observed in diabetes.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Giugliano D, Ceriello A, Paolisso G (1996) Oxidative stress and diabetic vascular complications. Diabetes Care 19(3):257–267

    Article  CAS  PubMed  Google Scholar 

  2. Koya D, King GL (1998) Protein kinase C activation and the development of diabetic complications. Diabetes 47(6):859–866

    Article  CAS  PubMed  Google Scholar 

  3. Rodbell M, Krans HM, Pohl SL, Birnbaumer L (1971) The glucagon-sensitive adenyl cyclase system in plasma membranes of rat liver. IV. Effects of guanylnucleotides on binding of 125I-glucagon. J Biol Chem 246(6):1872–1876

    CAS  PubMed  Google Scholar 

  4. Cockcroft S, Gomperts BD (1985) Role of guanine nucleotide binding protein in the activation of polyphosphoinositide phosphodiesterase. Nature 314(6011):534–536

    Article  CAS  Google Scholar 

  5. Litosch I, Wallis C, Fain JN (1985) 5-Hydroxytryptamine stimulates inositol phosphate production in a cell-free system from blowfly salivary glands. Evidence for a role of GTP in coupling receptor activation to phosphoinositide breakdown. J Biol Chem 260(9):5464–5471

    CAS  PubMed  Google Scholar 

  6. Breitwieser GE, Szabo G (1985) Uncoupling of cardiac muscarinic and beta-adrenergic receptors from ion channels by a guanine nucleotide analogue. Nature 317(6037):538–540

    Article  CAS  Google Scholar 

  7. Pfaffinger PJ, Martin JM, Hunter DD, Nathanson NM, Hille B (1985) GTP-binding proteins couple cardiac muscarinic receptors to a K channel. Nature 317(6037):536–538

    Article  CAS  Google Scholar 

  8. Gilman AG (1984) G proteins and dual control of adenylate cyclase. Cell 36(3):577–579. doi:0092-8674(84)90336-2 [pii]

    Article  CAS  PubMed  Google Scholar 

  9. Bray P, Carter A, Simons C, Guo V, Puckett C, Kamholz J, Spiegel A, Nirenberg M (1986) Human cDNA clones for four species of G alpha s signal transduction protein. Proc Natl Acad Sci U S A 83(23):8893–8897

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Murakami T, Yasuda H (1986) Rat heart cell membranes contain three substrates for cholera toxin-catalyzed ADP-ribosylation and a single substrate for pertussis toxin-catalyzed ADP-ribosylation. Biochem Biophys Res Commun 138(3):1355–1361. doi:S0006-291X(86)80432-6 [pii]

    Article  CAS  PubMed  Google Scholar 

  11. Robishaw JD, Smigel MD, Gilman AG (1986) Molecular basis for two forms of the G protein that stimulates adenylate cyclase. J Biol Chem 261(21):9587–9590

    CAS  PubMed  Google Scholar 

  12. Spiegel AM (1987) Signal transduction by guanine nucleotide binding proteins. Mol Cell Endocrinol 49(1):1–16

    Article  CAS  PubMed  Google Scholar 

  13. Stryer L, Bourne HR (1986) G proteins: a family of signal transducers. Annu Rev Cell Biol 2:391–419. doi:10.1146/annurev.cb.02.110186.002135

    Article  CAS  PubMed  Google Scholar 

  14. Wankerl M, Schwartz K (1995) Calcium transport proteins in the nonfailing and failing heart: gene expression and function. J Mol Med 73(10):487–496

    Article  CAS  PubMed  Google Scholar 

  15. Yatani A, Brown AM (1989) Rapid beta-adrenergic modulation of cardiac calcium channel currents by a fast G protein pathway. Science 245(4913):71–74

    Article  CAS  PubMed  Google Scholar 

  16. Itoh H, Kozasa T, Nagata S, Nakamura S, Katada T, Ui M, Iwai S, Ohtsuka E, Kawasaki H, Suzuki K et al (1986) Molecular cloning and sequence determination of cDNAs for alpha subunits of the guanine nucleotide-binding proteins Gs, Gi, and Go from rat brain. Proc Natl Acad Sci U S A 83(11):3776–3780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Itoh H, Toyama R, Kozasa T, Tsukamoto T, Matsuoka M, Kaziro Y (1988) Presence of three distinct molecular species of Gi protein alpha subunit. Structure of rat cDNAs and human genomic DNAs. J Biol Chem 263(14):6656–6664

    CAS  PubMed  Google Scholar 

  18. Jones DT, Reed RR (1987) Molecular cloning of five GTP-binding protein cDNA species from rat olfactory neuroepithelium. J Biol Chem 262(29):14241–14249

    CAS  PubMed  Google Scholar 

  19. Wong YH, Conklin BR, Bourne HR (1992) Gz-mediated hormonal inhibition of cyclic AMP accumulation. Science 255(5042):339–342

    Article  CAS  PubMed  Google Scholar 

  20. Kirsch GE, Yatani A, Codina J, Birnbaumer L, Brown AM (1988) Alpha-subunit of Gk activates atrial K+ channels of chick, rat, and guinea pig. Am J Phys 254(6 Pt 2):H1200–H1205

    CAS  Google Scholar 

  21. Simon MI, Strathmann MP, Gautam N (1991) Diversity of G proteins in signal transduction. Science 252(5007):802–808

    Article  CAS  PubMed  Google Scholar 

  22. Tang WJ, Gilman AG (1991) Type-specific regulation of adenylyl cyclase by G protein beta gamma subunits. Science 254(5037):1500–1503

    Article  CAS  PubMed  Google Scholar 

  23. Wickman KD, Iniguez-Lluhl JA, Davenport PA, Taussig R, Krapivinsky GB, Linder ME, Gilman AG, Clapham DE (1994) Recombinant G-protein beta gamma-subunits activate the muscarinic-gated atrial potassium channel. Nature 368(6468):255–257. doi:10.1038/368255a0

    Article  CAS  PubMed  Google Scholar 

  24. Wedegaertner PB, Wilson PT, Bourne HR (1995) Lipid modifications of trimeric G proteins. J Biol Chem 270(2):503–506

    Article  CAS  PubMed  Google Scholar 

  25. Taussig R, Iniguez-Lluhi JA, Gilman AG (1993) Inhibition of adenylyl cyclase by Gi alpha. Science 261(5118):218–221

    Article  CAS  PubMed  Google Scholar 

  26. Bushfield M, Griffiths SL, Murphy GJ, Pyne NJ, Knowler JT, Milligan G, Parker PJ, Mollner S, Houslay MD (1990) Diabetes-induced alterations in the expression, functioning and phosphorylation state of the inhibitory guanine nucleotide regulatory protein Gi-2 in hepatocytes. Biochem J 271(2):365–372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Caro JF, Raju MS, Caro M, Lynch CJ, Poulos J, Exton JH, Thakkar JK (1994) Guanine nucleotide binding regulatory proteins in liver from obese humans with and without type II diabetes: evidence for altered “cross-talk” between the insulin receptor and Gi-proteins. J Cell Biochem 54(3):309–319. doi:10.1002/jcb.240540307

    Article  CAS  PubMed  Google Scholar 

  28. Strassheim D, Palmer T, Houslay MD (1991) Genetically acquired diabetes: adipocyte guanine nucleotide regulatory protein expression and adenylate cyclase regulation. Biochim Biophys Acta 1096(2):121–126

    Article  CAS  PubMed  Google Scholar 

  29. Livingstone C, McLellan AR, McGregor MA, Wilson A, Connell JM, Small M, Milligan G, Paterson KR, Houslay MD (1991) Altered G-protein expression and adenylate cyclase activity in platelets of non-insulin-dependent diabetic (NIDDM) male subjects. Biochim Biophys Acta 1096(2):127–133

    Article  CAS  PubMed  Google Scholar 

  30. Hadjiconstantinou M, Qu ZX, Moroi-Fetters SE, Neff NH (1988) Apparent loss of Gi protein activity in the diabetic retina. Eur J Pharmacol 149(1–2):193–194

    Article  CAS  PubMed  Google Scholar 

  31. Hattori Y, Matsuda N, Sato A, Watanuki S, Tomioka H, Kawasaki H, Kanno M (2000) Predominant contribution of the G protein-mediated mechanism to NaF-induced vascular contractions in diabetic rats: association with an increased level of G(qalpha) expression. J Pharmacol Exp Ther 292(2):761–768

    CAS  PubMed  Google Scholar 

  32. Weber LP, Macleod KM (1997) Influence of streptozotocin diabetes on the alpha-1 adrenoceptor and associated G proteins in rat arteries. J Pharmacol Exp Ther 283(3):1469–1478

    CAS  PubMed  Google Scholar 

  33. Zheng XL, Guo J, Wang H, Malbon CC (1998) Expression of constitutively activated Gialpha2 in vivo ameliorates streptozotocin-induced diabetes. J Biol Chem 273(37):23649–23651

    Article  CAS  PubMed  Google Scholar 

  34. Moxham CM, Malbon CC (1996) Insulin action impaired by deficiency of the G-protein subunit G ialpha2. Nature 379(6568):840–844. doi:10.1038/379840a0

    Article  CAS  PubMed  Google Scholar 

  35. Hashim S, Liu YY, Wang R, Anand-Srivastava MB (2002) Streptozotocin-induced diabetes impairs G-protein linked signal transduction in vascular smooth muscle. Mol Cell Biochem 240(1–2):57–65

    Article  CAS  PubMed  Google Scholar 

  36. Griffiths SL, Knowler JT, Houslay MD (1990) Diabetes-induced changes in guanine-nucleotide-regulatory-protein mRNA detected using synthetic oligonucleotide probes. Eur J Biochem 193(2):367–374

    Article  CAS  PubMed  Google Scholar 

  37. Hashim S, Li Y, Nagakura A, Takeo S, Anand-Srivastava MB (2004) Modulation of G-protein expression and adenylyl cyclase signaling by high glucose in vascular smooth muscle. Cardiovasc Res 63(4):709–718. doi:10.1016/j.cardiores.2004.04.021

    Article  CAS  PubMed  Google Scholar 

  38. Li Y, Descorbeth M, Anand-Srivastava MB (2008) Role of oxidative stress in high glucose-induced decreased expression of Gialpha proteins and adenylyl cyclase signaling in vascular smooth muscle cells. Am J Phys Heart Circ Phys 294(6):H2845–H2854. doi:10.1152/ajpheart.91422.2007

    CAS  Google Scholar 

  39. Zhang Z, Apse K, Pang J, Stanton RC (2000) High glucose inhibits glucose-6-phosphate dehydrogenase via cAMP in aortic endothelial cells. J Biol Chem 275(51):40042–40047. doi:10.1074/jbc.M007505200

    Article  CAS  PubMed  Google Scholar 

  40. Yasuda H, Maeda K, Sonobe M, Kawabata T, Terada M, Hisanaga T, Taniguchi Y, Kikkawa R, Shigeta Y (1994) Metabolic effect of PGE1 analogue 01206.alpha CD on nerve Na(+)-K(+)-ATPase activity of rats with streptozocin-induced diabetes is mediated via cAMP: possible role of cAMP in diabetic neuropathy. Prostaglandins 47(5):367–378

    Article  CAS  PubMed  Google Scholar 

  41. Mancusi G, Hutter C, Baumgartner-Parzer S, Schmidt K, Schutz W, Sexl V (1996) High-glucose incubation of human umbilical-vein endothelial cells does not alter expression and function either of G-protein alpha-subunits or of endothelial NO synthase. Biochem J 315(Pt 1):281–287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hashim S, Li Y, Anand-Srivastava MB (2006) G protein-linked cell signaling and cardiovascular functions in diabetes/hyperglycemia. Cell Biochem Biophys 44(1):51–64. doi:10.1385/CBB:44:1:051

    Article  CAS  PubMed  Google Scholar 

  43. Anand-Srivastava MB (1989) Angiotensin II receptors negatively coupled to adenylate cyclase in rat myocardial sarcolemma. Involvement of inhibitory guanine nucleotide regulatory protein. Biochem Pharmacol 38(3):489–496

    Article  CAS  PubMed  Google Scholar 

  44. Anand-Srivastava MB, Srivastava AK, Cantin M (1987) Pertussis toxin attenuates atrial natriuretic factor-mediated inhibition of adenylate cyclase. Involvement of inhibitory guanine nucleotide regulatory protein. J Biol Chem 262(11):4931–4934

    CAS  PubMed  Google Scholar 

  45. Tucek S, Michal P, Vlachova V (2001) Dual effects of muscarinic M2 receptors on the synthesis of cyclic AMP in CHO cells: background and model. Life Sci 68(22–23):2501–2510

    Article  CAS  PubMed  Google Scholar 

  46. Kook H, Lee J, Kim SW, Kim SW, Baik YH (2002) Augmented natriuretic peptide-induced guanylyl cyclase activity and vasodilation in experimental hyperglycemic rats. Jpn J Pharmacol 88(2):167–173

    Article  CAS  PubMed  Google Scholar 

  47. Williams B, Tsai P, Schrier RW (1992) Glucose-induced downregulation of angiotensin II and arginine vasopressin receptors in cultured rat aortic vascular smooth muscle cells. Role of protein kinase C. J Clin Invest 90(5):1992–1999. doi:10.1172/JCI116079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Liu Y, Terata K, Rusch NJ, Gutterman DD (2001) High glucose impairs voltage-gated K(+) channel current in rat small coronary arteries. Circ Res 89(2):146–152

    Article  CAS  PubMed  Google Scholar 

  49. Hayashi S, Morishita R, Matsushita H, Nakagami H, Taniyama Y, Nakamura T, Aoki M, Yamamoto K, Higaki J, Ogihara T (2000) Cyclic AMP inhibited proliferation of human aortic vascular smooth muscle cells, accompanied by induction of p53 and p21. Hypertension 35(1 Pt 2):237–243

    Article  CAS  PubMed  Google Scholar 

  50. Fujita N, Furukawa Y, Du J, Itabashi N, Fujisawa G, Okada K, Saito T, Ishibashi S (2002) Hyperglycemia enhances VSMC proliferation with NF-kappaB activation by angiotensin II and E2F-1 augmentation by growth factors. Mol Cell Endocrinol 192(1–2):75–84

    Article  CAS  PubMed  Google Scholar 

  51. Baynes JW (1991) Role of oxidative stress in development of complications in diabetes. Diabetes 40(4):405–412

    Article  CAS  PubMed  Google Scholar 

  52. Baynes JW, Thorpe SR (1999) Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 48(1):1–9

    Article  CAS  PubMed  Google Scholar 

  53. Cai H, Harrison DG (2000) Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 87(10):840–844

    Article  CAS  PubMed  Google Scholar 

  54. Pacher P, Obrosova IG, Mabley JG, Szabo C (2005) Role of nitrosative stress and peroxynitrite in the pathogenesis of diabetic complications. Emerging new therapeutical strategies. Curr Med Chem 12(3):267–275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Pacher P, Szabo C (2006) Role of peroxynitrite in the pathogenesis of cardiovascular complications of diabetes. Curr Opin Pharmacol 6(2):136–141. doi:10.1016/j.coph.2006.01.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ceriello A, Mercuri F, Quagliaro L, Assaloni R, Motz E, Tonutti L, Taboga C (2001) Detection of nitrotyrosine in the diabetic plasma: evidence of oxidative stress. Diabetologia 44(7):834–838. doi:10.1007/s001250100529

    Article  CAS  PubMed  Google Scholar 

  57. Tannous M, Rabini RA, Vignini A, Moretti N, Fumelli P, Zielinski B, Mazzanti L, Mutus B (1999) Evidence for iNOS-dependent peroxynitrite production in diabetic platelets. Diabetologia 42(5):539–544. doi:10.1007/s001250051192

    Article  CAS  PubMed  Google Scholar 

  58. Pennathur S, Wagner JD, Leeuwenburgh C, Litwak KN, Heinecke JW (2001) A hydroxyl radical-like species oxidizes cynomolgus monkey artery wall proteins in early diabetic vascular disease. J Clin Invest 107(7):853–860. doi:10.1172/JCI11194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Berridge MJ (1987) Inositol trisphosphate as a second messenger in signal transduction. Ann N Y Acad Sci 494:39–51

    Article  CAS  PubMed  Google Scholar 

  60. Smrcka AV, Hepler JR, Brown KO, Sternweis PC (1991) Regulation of polyphosphoinositide-specific phospholipase C activity by purified Gq. Science 251(4995):804–807

    Article  CAS  PubMed  Google Scholar 

  61. Neves SR, Ram PT, Iyengar R (2002) G protein pathways. Science 296(5573):1636–1639. doi:10.1126/science.1071550

    Article  CAS  PubMed  Google Scholar 

  62. Akhter SA, Luttrell LM, Rockman HA, Iaccarino G, Lefkowitz RJ, Koch WJ (1998) Targeting the receptor-Gq interface to inhibit in vivo pressure overload myocardial hypertrophy. Science 280(5363):574–577

    Article  CAS  PubMed  Google Scholar 

  63. D’Angelo DD, Sakata Y, Lorenz JN, Boivin GP, Walsh RA, Liggett SB, Dorn GW 2nd (1997) Transgenic Galphaq overexpression induces cardiac contractile failure in mice. Proc Natl Acad Sci U S A 94(15):8121–8126

    Article  PubMed  PubMed Central  Google Scholar 

  64. Descorbeth M, Anand-Srivastava MB (2008) High glucose increases the expression of Gq/11alpha and PLC-beta proteins and associated signaling in vascular smooth muscle cells. Am J Phys Heart Circ Phys 295(5):H2135–H2142. doi:10.1152/ajpheart.00704.2008

    CAS  Google Scholar 

  65. Frey UH, Lieb W, Erdmann J, Savidou D, Heusch G, Leineweber K, Jakob H, Hense HW, Lowel H, Brockmeyer NH, Schunkert H, Siffert W (2008) Characterization of the GNAQ promoter and association of increased Gq expression with cardiac hypertrophy in humans. Eur Heart J 29(7):888–897. doi:10.1093/eurheartj/ehm618

    Article  CAS  PubMed  Google Scholar 

  66. Offermanns S, Zhao LP, Gohla A, Sarosi I, Simon MI, Wilkie TM (1998) Embryonic cardiomyocyte hypoplasia and craniofacial defects in G alpha q/G alpha 11-mutant mice. EMBO J 17(15):4304–4312. doi:10.1093/emboj/17.15.4304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Akhter SA, Milano CA, Shotwell KF, Cho MC, Rockman HA, Lefkowitz RJ, Koch WJ (1997) Transgenic mice with cardiac overexpression of alpha1B-adrenergic receptors. In vivo alpha1-adrenergic receptor-mediated regulation of beta-adrenergic signaling. J Biol Chem 272(34):21253–21259

    Article  CAS  PubMed  Google Scholar 

  68. Bogoyevitch MA, Andersson MB, Gillespie-Brown J, Clerk A, Glennon PE, Fuller SJ, Sugden PH (1996) Adrenergic receptor stimulation of the mitogen-activated protein kinase cascade and cardiac hypertrophy. Biochem J 314(Pt 1):115–121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Dorn GW 2nd, Tepe NM, Wu G, Yatani A, Liggett SB (2000) Mechanisms of impaired beta-adrenergic receptor signaling in G(alphaq)-mediated cardiac hypertrophy and ventricular dysfunction. Mol Pharmacol 57(2):278–287

    CAS  PubMed  Google Scholar 

  70. Hein L, Stevens ME, Barsh GS, Pratt RE, Kobilka BK, Dzau VJ (1997) Overexpression of angiotensin AT1 receptor transgene in the mouse myocardium produces a lethal phenotype associated with myocyte hyperplasia and heart block. Proc Natl Acad Sci U S A 94(12):6391–6396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Ichikawa KI, Hidai C, Okuda C, Kimata SI, Matsuoka R, Hosoda S, Quertermous T, Kawana M (1996) Endogenous endothelin-1 mediates cardiac hypertrophy and switching of myosin heavy chain gene expression in rat ventricular myocardium. J Am Coll Cardiol 27(5):1286–1291. doi:10.1016/0735-1097(95)00568-4

    Article  CAS  PubMed  Google Scholar 

  72. Sakata Y, Hoit BD, Liggett SB, Walsh RA, Dorn GW 2nd (1998) Decompensation of pressure-overload hypertrophy in G alpha q-overexpressing mice. Circulation 97(15):1488–1495

    Article  CAS  PubMed  Google Scholar 

  73. Kawaguchi H, Sano H, Iizuka K, Okada H, Kudo T, Kageyama K, Muramoto S, Murakami T, Okamoto H, Mochizuki N et al (1993) Phosphatidylinositol metabolism in hypertrophic rat heart. Circ Res 72(5):966–972

    Article  CAS  PubMed  Google Scholar 

  74. Keys JR, Greene EA, Koch WJ, Eckhart AD (2002) Gq-coupled receptor agonists mediate cardiac hypertrophy via the vasculature. Hypertension 40(5):660–666

    Article  CAS  PubMed  Google Scholar 

  75. Li Y, Hashim S, Anand-Srivastava MB (2006) Intracellular peptides of natriuretic peptide receptor-C inhibit vascular hypertrophy via Gqalpha/MAP kinase signaling pathways. Cardiovasc Res 72(3):464–472. doi:10.1016/j.cardiores.2006.08.012

    Article  CAS  PubMed  Google Scholar 

  76. Ohtsu H, Higuchi S, Shirai H, Eguchi K, Suzuki H, Hinoki A, Brailoiu E, Eckhart AD, Frank GD, Eguchi S (2008) Central role of Gq in the hypertrophic signal transduction of angiotensin II in vascular smooth muscle cells. Endocrinology 149(7):3569–3575. doi:10.1210/en.2007-1694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Goraya TY, Wilkins P, Douglas JG, Zhou J, Berti-Mattera LN (1995) Signal transduction alterations in peripheral nerves from streptozotocin-induced diabetic rats. J Neurosci Res 41(4):518–525. doi:10.1002/jnr.490410411

    Article  CAS  PubMed  Google Scholar 

  78. Inoguchi T, Battan R, Handler E, Sportsman JR, Heath W, King GL (1992) 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 U S A 89(22):11059–11063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Shiba T, Inoguchi T, Sportsman JR, Heath WF, Bursell S, King GL (1993) Correlation of diacylglycerol level and protein kinase C activity in rat retina to retinal circulation. Am J Phys 265(5 Pt 1):E783–E793

    CAS  Google Scholar 

  80. Tappia PS, Asemu G, Aroutiounova N, Dhalla NS (2004) Defective sarcolemmal phospholipase C signaling in diabetic cardiomyopathy. Mol Cell Biochem 261(1–2):193–199

    Article  CAS  PubMed  Google Scholar 

  81. Yang JM, Cho CH, Kong KA, Jang IS, Kim HW, Juhnn YS (1999) Increased expression of Galphaq protein in the heart of streptozotocin-induced diabetic rats. Exp Mol Med 31(4):179–184. doi:10.1038/emm.1999.29

    Article  CAS  PubMed  Google Scholar 

  82. Ramana KV, Friedrich B, Tammali R, West MB, Bhatnagar A, Srivastava SK (2005) Requirement of aldose reductase for the hyperglycemic activation of protein kinase C and formation of diacylglycerol in vascular smooth muscle cells. Diabetes 54(3):818–829

    Article  CAS  PubMed  Google Scholar 

  83. Williams B, Gallacher B, Patel H, Orme C (1997) Glucose-induced protein kinase C activation regulates vascular permeability factor mRNA expression and peptide production by human vascular smooth muscle cells in vitro. Diabetes 46(9):1497–1503

    Article  CAS  PubMed  Google Scholar 

  84. Ceccarelli F, Rosa Mazzoni M, Chakravarthy U (2001) Binding characteristics of ET receptors in retinal pericytes and effects of high glucose incubation. Curr Eye Res 23(4):263–270

    Article  CAS  PubMed  Google Scholar 

  85. Lin S, Kajimura M, Takeuchi K, Kodaira M, Hanai H, Nishimura M, Kaneko E (2000) Alterations of GTP-binding proteins (Gsalpha and Gq/11alpha) in gastric smooth muscle cells from streptozotocin-induced and WBN/Kob diabetic rats. Dig Dis Sci 45(8):1517–1524

    Article  CAS  PubMed  Google Scholar 

  86. Ergul A, Johansen JS, Stromhaug C, Harris AK, Hutchinson J, Tawfik A, Rahimi A, Rhim E, Wells B, Caldwell RW, Anstadt MP (2005) Vascular dysfunction of venous bypass conduits is mediated by reactive oxygen species in diabetes: role of endothelin-1. J Pharmacol Exp Ther 313(1):70–77. doi:10.1124/jpet.104.078105

    Article  CAS  PubMed  Google Scholar 

  87. Groop PH, Forsblom C, Thomas MC (2005) Mechanisms of disease: pathway-selective insulin resistance and microvascular complications of diabetes. Nat Clin Pract Endocrinol Metab 1(2):100–110. doi:10.1038/ncpendmet0046

    Article  CAS  PubMed  Google Scholar 

  88. Kyaw M, Yoshizumi M, Tsuchiya K, Kirima K, Suzaki Y, Abe S, Hasegawa T, Tamaki T (2002) Antioxidants inhibit endothelin-1 (1-31)-induced proliferation of vascular smooth muscle cells via the inhibition of mitogen-activated protein (MAP) kinase and activator protein-1 (AP-1). Biochem Pharmacol 64(10):1521–1531

    Article  CAS  PubMed  Google Scholar 

  89. Marrero MB, Schieffer B, Li B, Sun J, Harp JB, Ling BN (1997) Role of Janus kinase/signal transducer and activator of transcription and mitogen-activated protein kinase cascades in angiotensin II- and platelet-derived growth factor-induced vascular smooth muscle cell proliferation. J Biol Chem 272(39):24684–24690

    Article  CAS  PubMed  Google Scholar 

  90. Sachidanandam K, Harris A, Hutchinson J, Ergul A (2006) Microvascular versus macrovascular dysfunction in type 2 diabetes: differences in contractile responses to endothelin-1. Exp Biol Med 231(6):1016–1021

    CAS  Google Scholar 

  91. Sowers JR, Epstein M (1995) Diabetes mellitus and associated hypertension, vascular disease, and nephropathy. An update. Hypertension 26(6 Pt 1):869–879

    Article  CAS  PubMed  Google Scholar 

  92. Collier A, Leach JP, McLellan A, Jardine A, Morton JJ, Small M (1992) Plasma endothelinlike immunoreactivity levels in IDDM patients with microalbuminuria. Diabetes Care 15(8):1038–1040

    Article  CAS  PubMed  Google Scholar 

  93. Hargrove GM, Dufresne J, Whiteside C, Muruve DA, Wong NC (2000) Diabetes mellitus increases endothelin-1 gene transcription in rat kidney. Kidney Int 58(4):1534–1545. doi:10.1046/j.1523-1755.2000.00315.x

    Article  CAS  PubMed  Google Scholar 

  94. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD (1993) The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 329(20):1456–1462. doi:10.1056/NEJM199311113292004

    Article  CAS  PubMed  Google Scholar 

  95. Keynan S, Khamaisi M, Dahan R, Barnes K, Jackson CD, Turner AJ, Raz I (2004) Increased expression of endothelin-converting enzyme-1c isoform in response to high glucose levels in endothelial cells. J Vasc Res 41(2):131–140. doi:10.1159/000077132

    Article  CAS  PubMed  Google Scholar 

  96. Lavrentyev EN, Estes AM, Malik KU (2007) Mechanism of high glucose induced angiotensin II production in rat vascular smooth muscle cells. Circ Res 101(5):455–464. doi:10.1161/CIRCRESAHA.107.151852

    Article  CAS  PubMed  Google Scholar 

  97. Park JY, Takahara N, Gabriele A, Chou E, Naruse K, Suzuma K, Yamauchi T, Ha SW, Meier M, Rhodes CJ, King GL (2000) Induction of endothelin-1 expression by glucose: an effect of protein kinase C activation. Diabetes 49(7):1239–1248

    Article  CAS  PubMed  Google Scholar 

  98. Touyz RM, Yao G, Viel E, Amiri F, Schiffrin EL (2004) Angiotensin II and endothelin-1 regulate MAP kinases through different redox-dependent mechanisms in human vascular smooth muscle cells. J Hypertens 22(6):1141–1149

    Article  CAS  PubMed  Google Scholar 

  99. Kunisaki M, Bursell SE, Umeda F, Nawata H, King GL (1994) Normalization of diacylglycerol-protein kinase C activation by vitamin E in aorta of diabetic rats and cultured rat smooth muscle cells exposed to elevated glucose levels. Diabetes 43(11):1372–1377

    Article  CAS  PubMed  Google Scholar 

  100. Descorbeth M, Anand-Srivastava MB (2010) Role of oxidative stress in high-glucose- and diabetes-induced increased expression of Gq/11alpha proteins and associated signaling in vascular smooth muscle cells. Free Radic Biol Med 49(9):1395–1405. doi:10.1016/j.freeradbiomed.2010.07.023

    Article  CAS  PubMed  Google Scholar 

  101. Atef ME, Anand-Srivastava MB (2016) Oxidative stress contributes to the enhanced expression of Gqalpha/PLCbeta1 proteins and hypertrophy of VSMC from SHR: role of growth factor receptor transactivation. Am J Phys Heart Circ Phys 310(5):H608–H618. doi:10.1152/ajpheart.00659.2015

    Google Scholar 

  102. Li Y, Levesque LO, Anand-Srivastava MB (2010) Epidermal growth factor receptor transactivation by endogenous vasoactive peptides contributes to hyperproliferation of vascular smooth muscle cells of SHR. Am J Phys Heart Circ Phys 299(6):H1959–H1967. doi:10.1152/ajpheart.00526.2010

    CAS  Google Scholar 

  103. Akiyama N, Naruse K, Kobayashi Y, Nakamura N, Hamada Y, Nakashima E, Matsubara T, Oiso Y, Nakamura J (2008) High glucose-induced upregulation of Rho/Rho-kinase via platelet-derived growth factor receptor-beta increases migration of aortic smooth muscle cells. J Mol Cell Cardiol 45(2):326–332. doi:10.1016/j.yjmcc.2008.04.006

    Article  CAS  PubMed  Google Scholar 

  104. Inaba T, Ishibashi S, Gotoda T, Kawamura M, Morino N, Nojima Y, Kawakami M, Yazaki Y, Yamada N (1996) Enhanced expression of platelet-derived growth factor-beta receptor by high glucose. Involvement of platelet-derived growth factor in diabetic angiopathy. Diabetes 45(4):507–512

    Article  CAS  PubMed  Google Scholar 

  105. Konishi A, Berk BC (2003) Epidermal growth factor receptor transactivation is regulated by glucose in vascular smooth muscle cells. J Biol Chem 278(37):35049–35056. doi:10.1074/jbc.M304913200

    Article  CAS  PubMed  Google Scholar 

  106. Yamaguchi H, Igarashi M, Hirata A, Sugae N, Tsuchiya H, Jimbu Y, Tominaga M, Kato T (2004) Altered PDGF-BB-induced p38 MAP kinase activation in diabetic vascular smooth muscle cells: roles of protein kinase C-delta. Arterioscler Thromb Vasc Biol 24(11):2095–2101. doi:10.1161/01.ATV.0000144009.35400.65

    Article  CAS  PubMed  Google Scholar 

  107. Belmadani S, Palen DI, Gonzalez-Villalobos RA, Boulares HA, Matrougui K (2008) Elevated epidermal growth factor receptor phosphorylation induces resistance artery dysfunction in diabetic db/db mice. Diabetes 57(6):1629–1637. doi:10.2337/db07-0739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Chan KC, Wang CJ, Ho HH, Chen HM, Huang CN (2008) Simvastatin inhibits cell cycle progression in glucose-stimulated proliferation of aortic vascular smooth muscle cells by up-regulating cyclin dependent kinase inhibitors and p53. Pharmacol Res 58(3–4):247–256. doi:10.1016/j.phrs.2008.08.005

    Article  CAS  PubMed  Google Scholar 

  109. Jeong HY, Jeong HY, Kim CD (2004) p22phox-derived superoxide mediates enhanced proliferative capacity of diabetic vascular smooth muscle cells. Diabetes Res Clin Pract 64(1):1–10. doi:10.1016/j.diabres.2003.10.004

    Article  CAS  PubMed  Google Scholar 

  110. Ling HY, Hu B, Wang BX, Zu XY, Feng SD, Ou HS, Zhou SH, Liao DF (2008) Effects of rosiglitazone on the proliferation of vascular smooth muscle cell induced by high glucose. Cardiovasc Drugs Ther 22(6):453–460. doi:10.1007/s10557-008-6127-6

    Article  CAS  PubMed  Google Scholar 

  111. Campbell M, Allen WE, Silversides JA, Trimble ER (2003) Glucose-induced phosphatidylinositol 3-kinase and mitogen-activated protein kinase-dependent upregulation of the platelet-derived growth factor-beta receptor potentiates vascular smooth muscle cell chemotaxis. Diabetes 52(2):519–526

    Article  CAS  PubMed  Google Scholar 

  112. Kawano M, Koshikawa T, Kanzaki T, Morisaki N, Saito Y, Yoshida S (1993) Diabetes mellitus induces accelerated growth of aortic smooth muscle cells: association with overexpression of PDGF beta-receptors. Eur J Clin Investig 23(2):84–90

    Article  CAS  Google Scholar 

  113. Nakamura J, Kasuya Y, Hamada Y, Nakashima E, Naruse K, Yasuda Y, Kato K, Hotta N (2001) Glucose-induced hyperproliferation of cultured rat aortic smooth muscle cells through polyol pathway hyperactivity. Diabetologia 44(4):480–487. doi:10.1007/s001250051646

    Article  CAS  PubMed  Google Scholar 

  114. Kim TJ, Lee JH, Lee JJ, Yu JY, Hwang BY, Ye SK, Shujuan L, Gao L, Pyo MY, Yun YP (2008) Corynoxeine isolated from the hook of Uncaria rhynchophylla inhibits rat aortic vascular smooth muscle cell proliferation through the blocking of extracellular signal regulated kinase 1/2 phosphorylation. Biol Pharm Bull 31(11):2073–2078

    Article  CAS  PubMed  Google Scholar 

  115. Radhakrishnan Y, Maile LA, Ling Y, Graves LM, Clemmons DR (2008) Insulin-like growth factor-I stimulates Shc-dependent phosphatidylinositol 3-kinase activation via Grb2-associated p85 in vascular smooth muscle cells. J Biol Chem 283(24):16320–16331. doi:10.1074/jbc.M801687200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Wang Y, Yan T, Wang Q, Wang W, Xu J, Wu X, Ji H (2008) PKC-dependent extracellular signal-regulated kinase 1/2 pathway is involved in the inhibition of Ib on AngiotensinII-induced proliferation of vascular smooth muscle cells. Biochem Biophys Res Commun 375(1):151–155. doi:10.1016/j.bbrc.2008.07.137

    Article  CAS  PubMed  Google Scholar 

  117. Campbell M, Allen WE, Sawyer C, Vanhaesebroeck B, Trimble ER (2004) Glucose-potentiated chemotaxis in human vascular smooth muscle is dependent on cross-talk between the PI3K and MAPK signaling pathways. Circ Res 95(4):380–388. doi:10.1161/01.RES.0000138019.82184.5d

    Article  CAS  PubMed  Google Scholar 

  118. Belmadani S, Zerfaoui M, Boulares HA, Palen DI, Matrougui K (2008) Microvessel vascular smooth muscle cells contribute to collagen type I deposition through ERK1/2 MAP kinase, alphavbeta3-integrin, and TGF-beta1 in response to ANG II and high glucose. Am J Phys Heart Circ Phys 295(1):H69–H76. doi:10.1152/ajpheart.00341.2008

    CAS  Google Scholar 

  119. Descorbeth M, Anand-Srivastava MB (2010) Role of growth factor receptor transactivation in high glucose-induced increased levels of Gq/11alpha and signaling in vascular smooth muscle cells. J Mol Cell Cardiol 49(2):221–233. doi:10.1016/j.yjmcc.2009.12.010

    Article  CAS  PubMed  Google Scholar 

  120. Kim J, Lee CK, Park HJ, Kim HJ, So HH, Lee KS, Lee HM, Roh HY, Choi WS, Park TK, Kim B (2006) Epidermal growth factor induces vasoconstriction through the phosphatidylinositol 3-kinase-mediated mitogen-activated protein kinase pathway in hypertensive rats. J Pharmacol Sci 101(2):135–143

    Article  CAS  PubMed  Google Scholar 

  121. Lee CK, Lee HM, Kim HJ, Park HJ, Won KJ, Roh HY, Choi WS, Jeon BH, Park TK, Kim B (2007) Syk contributes to PDGF-BB-mediated migration of rat aortic smooth muscle cells via MAPK pathways. Cardiovasc Res 74(1):159–168. doi:10.1016/j.cardiores.2007.01.012

    Article  CAS  PubMed  Google Scholar 

  122. Son DJ, Kang J, Kim TJ, Song HS, Sung KJ, Yun DY, Hong JT (2007) Melittin, a major bioactive component of bee venom toxin, inhibits PDGF receptor beta-tyrosine phosphorylation and downstream intracellular signal transduction in rat aortic vascular smooth muscle cells. J Toxicol Environ Health A 70(15–16):1350–1355. doi:10.1080/15287390701428689

    Article  CAS  PubMed  Google Scholar 

  123. Zhang LJ, Ma WD, Yang Y, Wang RM, Chen P, Yan JB, Li Q, Li DD, Yang F (2008) AcSDKP attenuates PDGF-induced cardiac fibroblasts proliferation and collagen expression: role of extracellular regulated protein kinase 1/2 pathway. Zhonghua Xin Xue Guan Bing Za Zhi 36(5):444–448

    PubMed  Google Scholar 

  124. Atef ME, Anand-Srivastava MB (2014) Enhanced expression of Gqalpha and PLC-beta1 proteins contributes to vascular smooth muscle cell hypertrophy in SHR: role of endogenous angiotensin II and endothelin-1. Am J Phys Cell Phys 307(1):C97–106. doi:10.1152/ajpcell.00337.2013

    Article  CAS  Google Scholar 

  125. Atef ME, Anand-Srivastava MB (2016) Role of PKCdelta in enhanced expression of Gqalpha/PLCbeta1 proteins and VSMC hypertrophy in spontaneously hypertensive rats. PLoS One 11(7):e0157955. doi:10.1371/journal.pone.0157955

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  126. Saito S, Frank GD, Mifune M, Ohba M, Utsunomiya H, Motley ED, Inagami T, Eguchi S (2002) Ligand-independent trans-activation of the platelet-derived growth factor receptor by reactive oxygen species requires protein kinase C-delta and c-Src. J Biol Chem 277(47):44695–44700. doi:10.1074/jbc.M208332200

    Article  CAS  PubMed  Google Scholar 

  127. Suzaki Y, Yoshizumi M, Kagami S, Nishiyama A, Ozawa Y, Kyaw M, Izawa Y, Kanematsu Y, Tsuchiya K, Tamaki T (2004) BMK1 is activated in glomeruli of diabetic rats and in mesangial cells by high glucose conditions. Kidney Int 65(5):1749–1760. doi:10.1111/j.1523-1755.2004.00576.x

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology and Physiology, Faculty of Medicine, University of Montreal, C.P. 6128, Succ. Centre-ville, Montréal, Québec, H3C 3J7, Canada

    Madhu B. Anand-Srivastava Ph.D.

Authors
  1. Madhu B. Anand-Srivastava Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Madhu B. Anand-Srivastava Ph.D. .

Editor information

Editors and Affiliations

  1. Division of Cardiovascular Diseases and Diabetes Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India

    C.C. Kartha

  2. Division of Cardiovascular Diseases and Diabetes Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India

    Surya Ramachandran

  3. Translational Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India

    Radhakrishna M. Pillai

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Anand-Srivastava, M.B. (2017). G-Proteins in Vascular Complications of Diabetes. In: Kartha, C., Ramachandran, S., Pillai, R. (eds) Mechanisms of Vascular Defects in Diabetes Mellitus. Advances in Biochemistry in Health and Disease, vol 17. Springer, Cham. https://doi.org/10.1007/978-3-319-60324-7_13

Download citation

Publish with us

Policies and ethics

Search

Navigation