The Roles of cAMP and G Protein Signaling in Oxidative Stress-Induced Cardiovascular Dysfunction

  • Soumya Saha
  • Zhenquan Jia
  • Dongmin Liu
  • Hara P. MisraEmail author
Part of the Oxidative Stress in Applied Basic Research and Clinical Practice book series (OXISTRESS)


Cyclic adenosine monophosphate (cAMP) is a second messenger that plays a vital role in numerous biological processes. It serves as an intracellular signal transducer in many different organisms, exerting its effect through gene expression. In addition to its effects on intermediary metabolism, it has profound effects on cellular events, including growth stimulation, cell differentiation, and development. It mediates the action of many hormones acting through the cAMP response element (CRE) at gene levels. The levels of intracellular cAMP are regulated by Adenylyl cyclase (AC) and phosphodiesterase that catalyze the formation and breakdown of cAMP, respectively. Abnormalities in cAMP levels have been implicated in the pathogenesis of vascular diseases including hypertension. Increased levels of cAMP have been shown to have anti-inflammatory and tissue-protective effects. Reactive oxygen species (ROS) that cause oxidative stress have been shown to play a major role in the initial stage of cardiovascular diseases, including hypertension, where the role of cAMP has been implicated. Although the role of cAMP-signaling during hypertension is well known, its effects on oxidative stress protection are not fully understood. Two different signaling pathways have been suggested where cAMP could play a major role in causing hypertension: (1) lowering the cAMP levels, by angiotensin II, induces ROS production that leads to over expression of Giα protein, which consequently exerts hypertensive effects, and (2) increased levels of cAMP is known to attenuate the NADPH oxidase activity in cells, resulting in decreased oxidative stress, which, in turn, would decrease hypertension. However, in hyperglycemic state, it was proposed that an altered Gi protein expression causes accumulation of cAMP that leads to oxidative stress, thus resulting in hypertension. Regardless of the actual mechanism of action, it is apparent that cAMP and G protein signaling are associated with oxidative stress and play an important role in the pathogenesis of hypertension and hyperglycemia.


cAMP CVD G protein Oxidative stress 


  1. 1.
    Erdogan, S., Aslantas, O., Celik, S., Atik, E. (2008) The effects of increased cAMP content on inflammation, oxidative stress and PDE4 transcripts during Brucella melitensis infection Res Vet Sci 84, 18–25.Google Scholar
  2. 2.
    Abramovitch, R., Tavor, E., Jacob-Hirsch, J., et al. (2004) A pivotal role of cyclic AMP-responsive element binding protein in tumor progression Cancer Res 64, 1338–46.Google Scholar
  3. 3.
    Triner, L., Vulliemoz, Y., Verosky, M., Habif, D. V., Nahas, G. G. (1972) Adenyl cyclase-phosphodiesterase system in arterial smooth muscle Life Sci I 11, 817–24.Google Scholar
  4. 4.
    Katz, A. M., Tada, M., Kirchberger, M. A. (1975) Control of calcium transport in the myocardium by the cyclic AMP-Protein kinase system Adv Cyclic Nucleotide Res 5, 453–72.Google Scholar
  5. 5.
    Fleming, J. W., Wisler, P. L., Watanabe, A. M. (1992) Signal transduction by G proteins in cardiac tissues Circulation 85, 420–33.Google Scholar
  6. 6.
    Anand-Srivastava, M. B. (2005) Natriuretic peptide receptor-C signaling and regulation Peptides 26, 1044–59.Google Scholar
  7. 7.
    Hobbs, A., Foster, P., Prescott, C., Scotland, R., Ahluwalia, A. (2004) Natriuretic peptide receptor-C regulates coronary blood flow and prevents myocardial ischemia/reperfusion injury: novel cardioprotective role for endothelium-derived C-type natriuretic peptide Circulation 110, 1231–5.Google Scholar
  8. 8.
    Henschke, P. N., Elliott, S. J. (1995) Oxidized glutathione decreases luminal Ca2+ content of the endothelial cell ins(1,4,5)P3-sensitive Ca2+ store Biochem J 312 ( Pt 2), 485–9.Google Scholar
  9. 9.
    Paravicini, T. M., Touyz, R. M. (2006) Redox signaling in hypertension Cardiovasc Res 71, 247–58.Google Scholar
  10. 10.
    Finkel, T. (1998) Oxygen radicals and signaling Curr Opin Cell Biol 10, 248–53.Google Scholar
  11. 11.
    Rhee, S. G. (1999) Redox signaling: hydrogen peroxide as intracellular messenger Exp Mol Med 31, 53–9.Google Scholar
  12. 12.
    Zheng, M., Aslund, F., Storz, G. (1998) Activation of the OxyR transcription factor by reversible disulfide bond formation Science 279, 1718–21.Google Scholar
  13. 13.
    Greenberg, J. T., Monach, P., Chou, J. H., Josephy, P. D., Demple, B. (1990) Positive control of a global antioxidant defense regulon activated by superoxide-generating agents in Escherichia coli Proc Natl Acad Sci U S A 87, 6181–5.Google Scholar
  14. 14.
    Thannickal, V. J., Fanburg, B. L. (2000) Reactive oxygen species in cell signaling AmJ Physiol Lung Cell Mol Physiol 279, L1005–28.Google Scholar
  15. 15.
    Ushio-Fukai, M., Alexander, R. W. (2004) Reactive oxygen species as mediators of angiogenesis signaling: role of NAD(P)H oxidase Mol Cell Biochem 264, 85–97.Google Scholar
  16. 16.
    Kojda, G., Harrison, D. (1999) Interactions between NO and reactive oxygen species: pathophysiological importance in atherosclerosis, hypertension, diabetes and heart failure Cardiovasc Res 43, 562–71.Google Scholar
  17. 17.
    Rajagopalan, S., Kurz, S., Munzel, T., et al. (1996) Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone J Clin Invest 97, 1916–23.Google Scholar
  18. 18.
    Tong, X., Schroder, K. (2009) NADPH oxidases are responsible for the failure of nitric oxide to inhibit migration of smooth muscle cells exposed to high glucose Free Radic Biol Med 47, 1578–83.Google Scholar
  19. 19.
    Zalba, G., Beaumont, F. J., San Jose, G., et al. (2000) Vascular NADH/NADPH oxidase is involved in enhanced superoxide production in spontaneously hypertensive rats Hypertension 35, 1055–61.Google Scholar
  20. 20.
    Park, J. B., Touyz, R. M., Chen, X., Schiffrin, E. L. (2002) Chronic treatment with a superoxide dismutase mimetic prevents vascular remodeling and progression of hypertension in salt-loaded stroke-prone spontaneously hypertensive rats Am J Hypertens 15, 78–84.Google Scholar
  21. 21.
    Higashi, Y., Sasaki, S., Nakagawa, K., Matsuura, H., Oshima, T., Chayama, K. (2002) Endothelial function and oxidative stress in renovascular hypertension N Engl J Med 346, 1954–62.Google Scholar
  22. 22.
    Chabrashvili, T., Tojo, A., Onozato, M. L., et al. (2002) Expression and cellular localization of classic NADPH oxidase subunits in the spontaneously hypertensive rat kidney Hypertension 39, 269–74.Google Scholar
  23. 23.
    Wang, J. F., Zhang, X., Groopman, J. E. (2004) Activation of vascular endothelial growth factor receptor-3 and its downstream signaling promote cell survival under oxidative stressJ Biol Chem 279, 27088–97.Google Scholar
  24. 24.
    Hussain, S. P., Hofseth, L. J., Harris, C. C. (2003) Radical causes of cancer Nat Rev Cancer 3, 276–85.Google Scholar
  25. 25.
    Redon, J., Oliva, M. R., Tormos, C., et al. (2003) Antioxidant activities and oxidative stress byproducts in human hypertension Hypertension 41, 1096–101.Google Scholar
  26. 26.
    Nathan, C. (1992) Nitric oxide as a secretory product of mammalian cells FASEB J 6, 3051–64.Google Scholar
  27. 27.
    MacMicking, J. D., Nathan, C., Hom, G., et al. (1995) Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase Cell 81, 641–50.Google Scholar
  28. 28.
    Landmesser, U., Dikalov, S., Price, S. R., et al. (2003) Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension J Clin Invest 111, 1201–9.Google Scholar
  29. 29.
    Abe, J. I., Che, W., Yoshizumi, M., et al. (2001) Bcr in vascular smooth muscle cells involvement of Ras and Raf-1 activation by Bcr Ann N Y Acad Sci 947, 341–3.Google Scholar
  30. 30.
    Abate, C., Patel, L., Rauscher, F. J., 3rd, Curran, T. (1990) Redox regulation of fos and jun DNA-binding activity in vitro Science 249, 1157–61.Google Scholar
  31. 31.
    Schmid, E., Hotz-Wagenblatt, A., Hacj, V., Droge, W. (1999) Phosphorylation of the insulin receptor kinase by phosphocreatine in combination with hydrogen peroxide: the structural basis of redox priming FASEB J 13, 1491–500.Google Scholar
  32. 32.
    Droge, W., Schulze-Osthoff, K., Mihm, S., et al. (1994) Functions of glutathione and glutathione disulfide in immunology and immunopathology FASEB J 8, 1131–8.Google Scholar
  33. 33.
    Das, S. K., White, A. C., Fanburg, B. L. (1992) Modulation of transforming growth factor-beta 1 antiproliferative effects on endothelial cells by cysteine, cystine, and N-acetylcysteine. J Clin Invest 90, 1649–56.Google Scholar
  34. 34.
    Cantin, A. M., Larivee, P., Begin, R. O. (1990) Extracellular glutathione suppresses human lung fibroblast proliferation Am J Respir Cell Mol Biol 3, 79–85.Google Scholar
  35. 35.
    Hirota, K., Matsui, M., Iwata, S., Nishiyama, A., Mori, K., Yodoi, J. (1997) AP-1 transcriptional activity is regulated by a direct association between thioredoxin and Ref-1 Proc Natl Acad Sci U S A 94, 3633–8.Google Scholar
  36. 36.
    Yamawaki, H., Haendeler, J., Berk, B. C. (2003) Thioredoxin: a key regulator of cardiovascular homeostasis Circ Res 93, 1029–33.Google Scholar
  37. 37.
    Li, Y., Descorbeth, M., Anand-Srivastava, M. B. (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 Physiol Heart Circ Physiol 294, H2845–54.Google Scholar
  38. 38.
    Li, Y., Lappas, G., Anand-Srivastava, M. B. (2007) Role of oxidative stress in angiotensin II-induced enhanced expression of Gi(alpha) proteins and adenylyl cyclase signaling in A10 vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 292, H1922–30.Google Scholar
  39. 39.
    Pearson, G., Robinson, F., Beers Gibson, T., et al. (2001) Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions Endocr Rev 22, 153–83.Google Scholar
  40. 40.
    Ge, C., Anand-Srivastava, M. B. (1998) Involvement of phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways in AII-mediated enhanced expression of Gi proteins in vascular smooth muscle cells Biochem Biophys Res Commun 251, 570–5.Google Scholar
  41. 41.
    Lappas, G., Daou, G. B., Anand-Srivastava, M. B. (2005) Oxidative stress contributes to the enhanced expression of Gialpha proteins and adenylyl cyclase signaling in vascular smooth muscle cells from spontaneously hypertensive rats J Hypertens 23, 2251–61.Google Scholar
  42. 42.
    Saha, S., Li, Y., Anand-Srivastava, M. B. (2008) Reduced levels of cyclic AMP contribute to the enhanced oxidative stress in vascular smooth muscle cells from spontaneously hypertensive rats Can J Physiol Pharmacol 86, 190–8.Google Scholar
  43. 43.
    Berger, C. E., Horrocks, B. R., Datta, H. K. (1998) cAMP-dependent inhibition is dominant in regulating superoxide production in the bone-resorbing osteoclasts J Endocrinol 158, 311–8.Google Scholar
  44. 44.
    Abdollahi, M., Bahreini-Moghadam, A., Emami, B., Fooladian, F., Zafari, K. (2003) Increasing intracellular cAMP and cGMP inhibits cadmium-induced oxidative stress in rat submandibular saliva Comp Biochem Physiol C Toxicol Pharmacol 135C, 331–6.Google Scholar
  45. 45.
    Marcil, J., Anand-Srivastava, M. B. (2001) Lymphocytes from spontaneously hypertensive rats exhibit enhanced adenylyl cyclase-Gi protein signaling Cardiovasc Res 49, 234–43.Google Scholar
  46. 46.
    Bassil, M., Anand-Srivastava, M. B. (2006) Nitric oxide modulates Gi-protein expression and adenylyl cyclase signaling in vascular smooth muscle cells Free Radic Biol Med 41, 1162–73.Google Scholar
  47. 47.
    Bassil, M., Li, Y., Anand-Srivastava, M. B. (2008) Peroxynitrite inhibits the expression of G(i)alpha protein and adenylyl cyclase signaling in vascular smooth muscle cells Am J Physiol Heart Circ Physiol 294, H775–84.Google Scholar
  48. 48.
    Saha, S., Li, Y., Lappas, G., Anand-Srivastava, M. B. (2008) Activation of natriuretic peptide receptor-C attenuates the enhanced oxidative stress in vascular smooth muscle cells from spontaneously hypertensive rats: implication of Gialpha protein J Mol Cell Cardiol 44, 336–44.Google Scholar
  49. 49.
    Marty, C., Kozasa, T., Quinn, M. T., Ye, R. D. (2006) Activation state-dependent interaction between Galphai and p67phox Mol Cell Biol 26, 5190–200.Google Scholar
  50. 50.
    Anand-Srivastava, M. B. (1988) Altered responsiveness of adenylate cyclase to adenosine and other agents in the myocardial sarcolemma and aorta of spontaneously-hypertensive rats Biochem Pharmacol 37, 3017–22.Google Scholar
  51. 51.
    Anand-Srivastava, M. B. (1992) Enhanced expression of inhibitory guanine nucleotide regulatory protein in spontaneously hypertensive rats. Relationship to adenylate cyclase inhibition Biochem J 288 (Pt 1), 79–85.Google Scholar
  52. 52.
    Liu, S., Ma, X., Gong, M., Shi, L., Lincoln, T., Wang, S. (2007) Glucose down-regulation of cGMP-dependent protein kinase I expression in vascular smooth muscle cells involves NAD(P)H oxidase-derived reactive oxygen species Free Radic Biol Med 42, 852–63.Google Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Soumya Saha
  • Zhenquan Jia
  • Dongmin Liu
  • Hara P. Misra
    • 1
    Email author
  1. 1.Edward Via Virginia College of Osteopathic MedicineBlacksburgUSA

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