Activation of Mitogen-Activated Protein Kinases and Protein Kinase B/Akt Signaling by Oxidative Stress in Vascular Smooth Muscle Cells: Involvement in Vascular Pathophysiology

  • Ashok K. Srivastava
  • Nihar R. Pandey
  • Antoine Blanc
Part of the Progress in Experimental Cardiology book series (PREC, volume 10)


Oxidative stress has been implicated in the pathogenesis of a host of vascular abnormalities such as atherosclerosis, hypertension and in restenosis followed by balloon angioplasty. However, the molecular mechanism by which oxidative stress causes these abnor-malities remains poorly characterized. Recent studies have shown that exposure of vascular smooth muscle cells (VSMC) with H2O2, to mimic oxidative stress, activates components of growth promoting and proliferative signal transduction pathways. These components include mitogen-activated protein kinases (MAPKs) and protein kinase B (PKB/Akt), and are believed to be key players mediating growth, proliferation, hypertrophy, migration, survival and death of VSMC. In this article, we provide a brief overview of the effect of H2O2 on MAPKs and PKB/Akt signaling in VSMC in relation to their potential role in the pathogenesis of vascular abnormalities.

Key words

VSMC mitogen-activated protein kinases protein kinase B vascular pathophysiology oxidative stress H2O2 


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  1. 1.
    Droge W. 2002. Free radicals in the physiological control of cell function. Physiol Rev 82:47–95.PubMedGoogle Scholar
  2. 2.
    Dhalla NS, Temsah RW, Netticaden T. 2000. Role of oxidative stress in cardiovascular disease. J Hypertens 18:655–673.PubMedCrossRefGoogle Scholar
  3. 3.
    Singal PK, Khaper N, Palace V, Kumar D. 1998. The role of oxidative stress in the genesis of heart disease. Cardiovas Res 40:426–432.CrossRefGoogle Scholar
  4. 4.
    Turrens JF. 1997. Superoxide production by the mitochondrial respiratory chain. Bio Sc Rep 17:3–8.CrossRefGoogle Scholar
  5. 5.
    Boveris A, Chance B. 1973. The mitochondrial generation of hydrogen peroxide: General properties and effect of hyperbasic oxygen. Biochem J 134:707–716.PubMedGoogle Scholar
  6. 6.
    Imalay JA, Chin SM, Lin S. 1988. Toxic DNA damage by hydrogen peroxide through the Fenton reaction in vivo and in vitro. Science 240:640–642.CrossRefGoogle Scholar
  7. 7.
    Haber F, Weiss JJ. 1934. The catalytic decomposition of hydrogen peroxide by iron salts. Proc R Soc Lond Ser A 147:332–335.CrossRefGoogle Scholar
  8. 8.
    Abe JI, Berk BC. 1998. Reactive oxygen species as mediators of signal transduction in cardiovascular disease. Trends in Cardiovas Med 8:59–64.CrossRefGoogle Scholar
  9. 9.
    Sundaresan M, Yu ZX, Ferrari VJ, Ironi K, Finkel T. 1995. Requirement for the generation of H2O2 for platelet-derived growth factor signal transduction. Science 270:296–299.PubMedCrossRefGoogle Scholar
  10. 10.
    Bae VS, Kang SW, Seo MS, Barnes IC, Tekle E, Chock PB, Rhee SG. 1997. Epidermal growth factor (EGF)-induced generation of hydrogen peroxide. Role in EGF receptor-mediated tyrosine phosphorylation. J Biol Chem 272:217–221.PubMedCrossRefGoogle Scholar
  11. 11.
    Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. 1994. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circulation 74:1141–1148.CrossRefGoogle Scholar
  12. 12.
    Mahadev K, Wu X, Zilbering A, Zhu L, Lawrence JT, Goldstein BJ. 2001. Hydrogen peroxide generated during cellular insulin signaling cascade in 3T3-L1 adipocytes. J Biol Chem 276:48662–48669.PubMedCrossRefGoogle Scholar
  13. 13.
    Lo YYC, Cruz TF. 1995. Involvement of reactive oxygen species in cytokines and growth factor induction of c-fos expression in chondrocytes. J Biol Chem 270:11727–11730.PubMedCrossRefGoogle Scholar
  14. 14.
    Lo YYC, Wong JMS, Cruz TF. 1996. Reactive oxygen species mediate cytokine activation of c-Jun NH2-terminal kinases. J Biol Chem 271:15703–15707.PubMedCrossRefGoogle Scholar
  15. 15.
    Seger R, Krebs EG. 1995. The MAPK signaling cascade. FASEB J 9:726–735.PubMedGoogle Scholar
  16. 16.
    Widman C, Gibson S, Jarpe MB, Johnson GL. 1999. Mitogen-activated protein kinase: conservation of a 3-kinase module from yeast to human. Physiol Rev 79:143–180.Google Scholar
  17. 17.
    Ip YT, Davis RJ. 1998. Signal transduction by c-Jun N-terminal kinase (JNK) from inflammation to development. Curr Opin Cell Biol 10:205–219.PubMedCrossRefGoogle Scholar
  18. 18.
    Force T, Bonventre JV. 1998. Growth factors and mitogen-activated protein kinases. Hypertension 31 (Part II):152–161.PubMedCrossRefGoogle Scholar
  19. 19.
    Davis RJ. 1993. The mitogen-activated protein kinase signal transduction pathway. J Biol Chem 268:14553–14556.PubMedGoogle Scholar
  20. 20.
    Denton RM, Tavare JM. 1995. Dose mitogen-activated protein kinases have a role in insulin action: The cases for and against. Eur J Biochem 227:597–611.PubMedCrossRefGoogle Scholar
  21. 21.
    Tan Y, Rouse J, Zhang A, Cariati S, Cohen P, Comb MJ. 1996. FGF and stress regulate CRJEB and ATF-1 via a pathway involving p38 MAP kinase and MAPKAP kinase-2. EMBO J 15:4629–4642.PubMedGoogle Scholar
  22. 22.
    Wang X, Rao D. 1996. Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD 153) by p38 MAP kinase. Science 272:1347.PubMedCrossRefGoogle Scholar
  23. 23.
    Gupta S, Campbell D, Derijand B, Davis RJ. 1995. Transcription factor AFT-2 regulation by the JNK signal transduction pathway. Science 267:389–393.PubMedCrossRefGoogle Scholar
  24. 24.
    Zinck R, Cahill MA, Kracht M, Sachsenmaier C, Hipskind RA, Nordheim A. 1995. Protein syn-thesis inhibitor reveals differential regulation of mitogen-activated protein kinase and stress-activated protein kinase pathways that converge on Elk-1. Mol Cell Biol 15:4930–4939.PubMedGoogle Scholar
  25. 25.
    Frodin M, Gammeltoft S. 1999. Role and regulation of 90kDa ribosomal S6 kinase (RSK) in signal transduction. Mol Cell Endocrinol 151:65–77.PubMedCrossRefGoogle Scholar
  26. 26.
    Bass AS, Berk BC. 1995. Differential activation of mitogen-activated protein kinases by H2O2 and O-2 in vascular smooth muscle cells. Cir Res 77:29–36.CrossRefGoogle Scholar
  27. 27.
    Rao GN. 1996. Hydrogen peroxide induces complex formation of SHC-Grb2-SOS with receptor tyrosine kinase and activates Ras and extracellular signal-regulated protein kinases group of mitogen-activated protein kinase. Oncogene 13:713–719.PubMedGoogle Scholar
  28. 28.
    Abe J, Kusuhara M, Ulevitch RJ, Berk BC, Lee J-D. 1996. Big mitogen-activated protein kinase 1 (BMK1) is a redox-sensitive kinase. J Biol Chem 271:16586–16590.PubMedCrossRefGoogle Scholar
  29. 29.
    Rao GN. 1997. Protein tyrosine kinase activity is required for oxidant-induced extracellular signal-regulated protein kinase activation and c-fos and c-Jun expression. Cell Signal 9:181–187.PubMedCrossRefGoogle Scholar
  30. 30.
    Zhang J, Jin N, Liu Y, Rhoades RA. 1998. Hydrogen peroxide stimulates extra-cellular signal-regulated protein kinase in pulmonary arterial smooth muscle cells. Am J Respir Cell Mol Biol 19: 324–332.PubMedCrossRefGoogle Scholar
  31. 31.
    Ushio-Fukai, Alexander RW, Akers M, Griendling KK. 1998. p38 mitogen-activated protein kinase is a critical component of the redox-sensitive signaling pathways by angiotensin II: role in vascular smooth muscle cell hypertrophy. J Biol Chem 273:15022–15029.PubMedCrossRefGoogle Scholar
  32. 32.
    Yoshizumi M, Abe J, Haendeler J, Huang Q, Berk BC. 2000. Src and Cas mediate JNK activation but not ERK1/2 and p38 kinases by reactive oxygen species. J Biol Chem 275:11706–11712.PubMedCrossRefGoogle Scholar
  33. 33.
    Guyton KZ, Liv Y, Gorospe M, Xu Q, Holbrook NJ. 1996. Activation of mitogen-activated protein kinase by H2O2. Role in cell survival following oxidant injury. J Biol Chem 271:4138–4142.PubMedCrossRefGoogle Scholar
  34. 34.
    Taher MM, Mahgouh MA, Abd-Elfattah ASA. 1998. Redox regulation of signal transduction in smooth muscle cells: distinct effects of PKC-down regulation and PKC inhibition on oxidant-induced MAP kinase. J Recept & Signal Trend Res 18:167–185.Google Scholar
  35. 35.
    Srivastava AK, Pandey SK. 2000. Stimulation of mitogen-activated protein kinases ERK-1 and ERK-2 by H2O2 in vascular smooth muscle cells. In: The Hypertrophied Heart, Takeda N, Nagao M and Dhalla NS (Eds). Boston, Kluwer Academic Publishers, pp. 197–206.CrossRefGoogle Scholar
  36. 36.
    Griendling KK, Sorescu D, Lassegue B, Ushio-Fukai M. 2000. Modulation of protein activity and gene expression by reactive oxygen species and their role in vascular physiology and pathology. Arterioscler Thromb Vas Biol 20:2175–2183.CrossRefGoogle Scholar
  37. 37.
    Chao A, Graves J, Reidy MA. 2000. Mitogen activated protein kinases mediated matrix metallo-proteinase-9 expression in vascular smooth muscle cells. Artenoscler Thromb Vas Biol 20:2527–2532.CrossRefGoogle Scholar
  38. 38.
    Bellacosa A, Testa JR, Staal SP, Tsichlis PN. 1991. A retroviral oncogene, akt, encoding a serine-threonine kinases containing an SH-2 like region. Science 254:274–277.PubMedCrossRefGoogle Scholar
  39. 39.
    Datta SR, Brunet A, Greenberg ME. 1999. Cellular survival: a play in three Akts. Genes Dev 13: 2905–2927.PubMedCrossRefGoogle Scholar
  40. 40.
    Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, Hemmings BA. 1996. Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J 15:5541–6551.Google Scholar
  41. 41.
    Alessi DR, James SR, Dowries CP, Holmes AB, Gaffeney PR, Reese CB, Cohen P. 1997. Characterization of a 3-phoshpoinositide-dependent protein kinase which phosphorylates and activates protein kinase B alpha. Curr Biol 7:261–269.PubMedCrossRefGoogle Scholar
  42. 42.
    Fruman DA, Meyers RE, Candey LC. 1998. Phosphoinositide kinase. Annu Rev Biochem 67: 481–507.PubMedCrossRefGoogle Scholar
  43. 43.
    Kozma SC, Thomas G. 2002. Regulation of cell size in growth, development and human disease: PI3K, PKB and S6K. Bio Essays 24:65–71.Google Scholar
  44. 44.
    Ushio-Fukai M, Alexander W, Akers M, Yin QQ, Fujio Y, Walsh K, Griendling KK. 1999. Reactive oxygen species mediate the activation of Akt/Protein kinase B by angiotensin II in vascular smooth muscle cells. J Biol Chem 274:22699–22764.PubMedCrossRefGoogle Scholar
  45. 45.
    Srivastava AK. 1998. Use of pharmacological inhibitors in elucidating the mechanism of insulin action. Trends Pharmacol Sci 19:205–209.PubMedCrossRefGoogle Scholar
  46. 46.
    Jin N, Hatton ND, Harrington MA, Xia X, Larsen SH, Rhoades RA. 2000. H2O2-induced EGR-1, FRA-1 and c-Jun gene expression is mediated by tyrosine kinase in aortic smooth muscle cells. Free Rad Biol Med 29:736–746.PubMedCrossRefGoogle Scholar
  47. 47.
    Abe J, Berk BC. 1999. Fyn and JAK2 mediate Ras activation by reactive oxygen species. J Biol Chem 274:21003–21010.PubMedCrossRefGoogle Scholar
  48. 48.
    Abe J, Okuda M, Huang Q, Yoshizumi M, Berk BC. 2000. Reactive oxygen species activate p90 ribosomal S6 kinase via Fyn and Ras. J Biol Chem 275:1739–1748.PubMedCrossRefGoogle Scholar
  49. 49.
    Lee SR, Kwon KS, Kim SR, Rhee SG. 1998. Reversible inactivation of protein tyrosine phosphatase IB in A431 cells stimulated with epidermal growth factor. J Biol Chem 273:15366–15372.PubMedCrossRefGoogle Scholar
  50. 50.
    Meng T-C, Fukada, Tonks NK. 2002. Reversible oxidation and inactivation of protein tyrosine phosphates in vivo. Mol Cell 9:387–399.PubMedCrossRefGoogle Scholar
  51. 51.
    Guam KC, Dixon JE. 1991. Evidence for protein tyrosine phosphatase catalysis via a cysteine-phosphate intermediate. J Biol Chem 266:17026–17030.Google Scholar
  52. 52.
    Brazil DP, Hemming BA. 2001. Ten years of protein kinase B signaling: a hard Akt to follow. Trends Biochem Sci 26:657–664.PubMedCrossRefGoogle Scholar
  53. 53.
    Roveri A, Coassin M, Maiorino M, Zamburlini A, Van Amesterdam FT, Raid F. 1992. Effect of hydrogen peroxide on calcium homeostasis in smooth muscle cells. Arch Biochem Biophys 297: 265–270.PubMedCrossRefGoogle Scholar
  54. 54.
    Yang ZW, Zheng T, Wang J, Zhang A, Altura BT, Altura BM. 1999. Hydrogen peroxide induces contraction and raises [Ca2+], in canine cerebral arterial smooth muscle: Participation of cellular signaling pathways. Naunyn Schmiedebergs Arch Pharmacol 360:646–653.PubMedCrossRefGoogle Scholar
  55. 55.
    Meyer TN, Gloy J, Hug MJ, greger R, Schollmeyer P, Pavenstadt H. 1996. Hydrogen peroxide increases the intracellular calcium activity in rat mesanglial cells in primary culture. Kidney Int 49:388–395.PubMedCrossRefGoogle Scholar
  56. 56.
    Qiu S, Stadman ER, Chock PB. 2000. Regulation of oxidative stress-induced calcium release by phosphatidylinositol 3-kinase and Bruton’s tyrosine kinase in B cells. Proc Natl Acad Sci 97: 7118–7123.CrossRefGoogle Scholar
  57. 57.
    Qin S, Chock PB. 2001. Bruton’s tyrosine kinase is essential for peroxide-induced calcium signaling. Biochemistry 40:8085–8091.PubMedCrossRefGoogle Scholar
  58. 58.
    González-Pacheco FR, Caramelo C, Castilla MA, Deudero JJP, Arias J, Yagüe S, Jiménez, Bragado R, Álvarez-Arroyo MV. 2002. Mechanism of vascular smooth muscle cells activation by hydrogen peroxide: role of phospholipase C gamma. Nephrol Dial Transplant 17:392–398.PubMedCrossRefGoogle Scholar
  59. 59.
    Pandey SK, Théberge J-F, Bernier M, Srivastava AK. 1999. Phosphatidylinositol 3-kinase requirement in activation of ras/C-raf-1/MEK/ERK and p70s6k signaling cascade by the insulinomimetic agent vanadyl sulfate. Biochemistry 38:14667–14675.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2004

Authors and Affiliations

  • Ashok K. Srivastava
    • 1
    • 2
  • Nihar R. Pandey
    • 1
    • 2
  • Antoine Blanc
    • 1
    • 2
  1. 1.Research Center-CHUM, Hôtel-DieuMontrealCanada
  2. 2.Department of MedicineUniversité de MontréalMontrealCanada

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