Current Hypertension Reports

, Volume 2, Issue 2, pp 167–173 | Cite as

Free radical production and angiotensin

  • Gunter Wolf


Angiotensin II (ANG II) has multiple effects on cardiovascular and renal cells, including vasoconstriction, cell growth, induction of proinflammatory cytokines, and profibrogenic actions. Recent studies provide evidence that ANG II could stimulate intracellular formation of reactive oxygen species (ROS) such as the superoxide anion (O2 -). This ANG II-mediated ROS formation exhibits different kinetic and lower absolute concentrations than those traditionally observed during the respiratory burst of phagocytic cells, but it likely involves similar membrane-bound NAD(P)Hoxidases. Current evidence suggests that ANG II, through AT1-receptor activation, upregulates several subunits of this multienzyme complex, resulting in an increase in intracellular O2-concentration. ROS are involved in several signal pathways, and redox-sensitive transcriptional factors (AP-1, NF-kB) have been characterized. ANG II-induced ROS play a pivotal role in several pathophysiologic situations of vascular and renal cells such as hypertension, endothelial dysfunction, nitrate tolerance, atherosclerosis, and cellular remodeling. Although these perceptions suggest that drugs interfering with ANG II effects (ACE inhibitors, AT1 -receptor antagonist) may serve as antioxidants, preventing vascular and renal changes, the clinical studies are not so straightforward. In fact, only specific risk groups, such as patients with diabetes mellitus or renal insufficiency, may benefit from ACE inhibitors, whereas hard endpoints showed no advantage for ACE inhibitors in patients with essential hypertension.


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References and Recommended Reading

  1. 1.
    Fridovich I: Superoxide anion radical (O2-•), superoxide dismutases, and related matters. J Biol Chem 1997, 272:18515–18517. This is an excellent review discussing current issues of reactive oxygen species research written by a pioneer in this field.PubMedCrossRefGoogle Scholar
  2. 2.
    Beckman JS, Koppenol WH: Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and the ugly. Am J Physiol 1996, 271:C1424-C1437.PubMedGoogle Scholar
  3. 3.
    Farber JL, Kyle ME, Coleman JB: Mechanisms of cell injury by activated oxygen species. Lab Invest 1990, 62:670–679.PubMedGoogle Scholar
  4. 4.
    Griendling KK, Ushio-Fukai M: NADH/NADPH oxidase. Trends Cardiovasc Med 1997, 7:301–307.CrossRefGoogle Scholar
  5. 5.
    Ushio-Fukai M, Zafari AM, Fukui T, et al.: p22phox is a critical component of the superoxide-generating NADH/NADPH oxidase system and regulates angiotensin II-induced hypertrophy in vascular smooth muscle cells. J Biol Chem 1996, 271:23317–23321. Important study demonstrating the pivotal role of p22phox in NAD(P)H-oxidase activation by angiotensin II.PubMedCrossRefGoogle Scholar
  6. 6.
    Hannken T, Schroeder R, Stahl RAK, Wolf G: Angiotensin II-mediated expression of p27Kip1 and induction of cellular hypertrophy in renal tubular cells depend on the generation of oxygen radicals. Kidney Int 1998, 54:1923–1933. This study is the first demonstration of angiotensin II-induced ROS formation in proximal tubular cells. Furthermore, this study links reactive oxygen species to events of cell cycle regulation by demonstrating that oxygen increases the p27Kip1, an inhibitor of cyclin/cyclin-dependent kinase complexes.PubMedCrossRefGoogle Scholar
  7. 7.
    Crawford K, Zbinden I, Amstad P, Cerutti P: Oxidant stress induces the proto-oncogenes c-fos and c-myc in mouse epidermal cells. Oncogene 1988, 3:27–32.Google Scholar
  8. 8.
    Shibanuma M, Kuroki T, Nose K:Induction of DNA replication and expression of proto-oncogenes c-myc and c-fos in quiescent Balb/3T3 cells by xanthine/xanthine oxidase. Oncogene 1988, 3:17–21.Google Scholar
  9. 9.
    Rao GN, Berk BC: Active oxygen species stimulate vascular smooth muscle cell growth and proto-oncogene expression. Circ Res 1992, 70:593–599.PubMedGoogle Scholar
  10. 10.
    Rao GN, Lassègue B, Griendling KK, Alexander RW: Hydrogen peroxide stimulates transcription of c-jun in vascular smooth muscle cells: role of arachidonic acid. Oncogene 1993, 8:2759–2764.PubMedGoogle Scholar
  11. 11.
    Rao GN, Lassègue B, Griendling KK, et al.: Hydrogen peroxideinduced c-fos expression is mediated by arachidonic acid release: role of protein kinase C. Nucleic Acids Res 1993, 21:1259–1263.PubMedCrossRefGoogle Scholar
  12. 12.
    Del Arco PG, Martinez-Martinez S, Calvo V, et al.: Antioxidants and AP-1 activation: a brief overview. Immunobiology 1997, 198:273–278.Google Scholar
  13. 13.
    Dalton TP, Shertzer HG, Puga A: Regulation of gene expression by reactive oxygen. Annu Rev Pharmacol Toxicol 1999, 39:67–101.PubMedCrossRefGoogle Scholar
  14. 14.
    Schreck R, Rieber P, Bauerle PA: Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kB transcription factor and HIV-1. EMBO J 1991, 10:2247–2225.PubMedGoogle Scholar
  15. 15.
    Piette J, Piret B, Bonizzi G, et al.: Multiple redox regulation in NF-kB transcription factor activation. Biol Chem 1997, 378:1237–1245.PubMedGoogle Scholar
  16. 16.
    Wung BS, Cheng JJ, Hsieh HJ, et al.: Cyclic strain-induced monocyte chemotatic protein-1 gene expression in endothelial cells involves reactive oxygen species activation of activator protein 1. Circ Res 1997, 81:1–7.PubMedGoogle Scholar
  17. 17.
    Suzuki YJ, Forman HJ, Sevanina A: Oxidants as stimulators of signal transduction. Free Radic Biol Med 1997, 22:269–285.PubMedCrossRefGoogle Scholar
  18. 18.
    Dreher D, Jornot L, Junod AF: Effects of hypoxanthine xanthine oxidase on Ca 2+ stores and protein synthesis in human endothelial cells. Circ Res 1995, 76:388–395.PubMedGoogle Scholar
  19. 19.
    Grover AK, Samson SE, Formin VP: Peroxide inactivates calcium pump in pig coronary artery. Am J Physiol 1992, 263:H537-H543.PubMedGoogle Scholar
  20. 20.
    Bass AS, Berk BC: Differential activation of mitogen-activated protein kinases by H 2O2 and O 2-in vascular smooth muscle cells. Cir Res 1995, 77:29–36.Google Scholar
  21. 21.
    Abe J, Takahashi M, Ishida M, et al.: c-SRC is required for oxidative stress-mediated activation of big mitogen-activated protein kinase (MNK1). J Biol Chem 1997, 272:20389–20394. Novel molecular mechanism how ROS induce mitogen-activated protein kinases.PubMedCrossRefGoogle Scholar
  22. 22.
    Laderoute KR, Webster KA: Hypoxia/reoxygenation stimulates jun kinase activity through redox signaling in cardiac myocytes. Cir Res 1997, 80:336–344.Google Scholar
  23. 23.
    Seko Y, Kazuyuki T, Ueki K, et al.: Hypoxia and hypoxia/ reoxygenation activate Raf-1, mitogen-activated protein kinase kinase, mitogen-activated protein kinases, and S6 kinase in cultured rat cardiac myocytes. Cir Res 1996, 78:82–90.Google Scholar
  24. 24.
    Ushio-Fukai M, Alexander RW, Akers M, Griendling KK: p38 mitogen-activated protein kinase is a critcial component of the redox-sensitive signaling pathways activated by angiotensin II: role in vascular smooth muscle cell hypertrophy. J Biol Chem 1998, 273:15022–15029. Important study providing evidence that angiotensin II-induced ROS activate p38 kinase and mediate vascular smooth muscle hypertrophy through this mechanism.PubMedCrossRefGoogle Scholar
  25. 25.
    Sullivan SG, Chiu DT, Errasfa M, et al.: Effects of H 2O2 on protein tyrosine phosphatase activity in HER14 cells. Free Radic Biol Med 1994, 16:399–403.PubMedCrossRefGoogle Scholar
  26. 26.
    Irani K, Xia Y, Zweier JL, et al.: Mitogenic signaling mediated by oxidants in ras-transformed fibroblasts. Science 1997, 275:1649–1652. Demonstration that ROS are components of signal transduction pathways that are altered in transformed cells leading to the uninhibited proliferation of cancer cells.PubMedCrossRefGoogle Scholar
  27. 27.
    Irani K, Goldschmidt-Clermont PJ: Ras, superoxide and signal transduction. Biochem Pharmacol 1998, 55:1339–1346.PubMedCrossRefGoogle Scholar
  28. 28.
    Abe JI, Berk BC: Reactive oxygen species as mediators of signal transduction in cardiovascular disease. Trends Cardiovasc Med 1998, 8:59–64.CrossRefGoogle Scholar
  29. 29.
    Kunsch C, Medford RM: Oxidative stress as a regulator of gene expression in the vasculature. Circ Res 1999, 85:753–766.PubMedGoogle Scholar
  30. 30.
    Wilson SK: Role of oxygen-derived free radicals in acute angiotensin II-induced hypertensive vascular disease in the ratfi Cir Res 1990, 66:722–734.Google Scholar
  31. 31.
    Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW: Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Cir Res 1994, 74:1141–1148.Google Scholar
  32. 32.
    Zafari AM, Ushio-Fukai M, Akers M, et al.: Role of NADH/ NADPH oxidase-derived H 2O2 in angiotensin II-induced vascular hypertrophy. Hypertension 1998, 32:488–495.PubMedGoogle Scholar
  33. 33.
    Jaimes EA, Galceran JM, Raij L: Angiotensin II induces superoxide anion production by mesangial cells. Kidney Int 1998, 54:775–784.PubMedCrossRefGoogle Scholar
  34. 34.
    Yanagitani Y, Rakugi H, Okamura A, et al.: Angiotensin II type I receptor-mediated peroxide production in human macrophages. Hypertension 1999, 33:335–339.PubMedGoogle Scholar
  35. 35.
    Pagano PJ, Clark JK, Cifuentes-Pagano ME, et al.: Localization of a constitutively active, phagocyte-like NADPH oxidase in rabbit aortic adventitia: enhancement by angiotensin II. Proc Natl Acad Sci USA 1997, 94:14483–14488. Evidence for an NAD(P)H-oxidase, localized in adventitial fibroblasts that is activated by angiotensin II.PubMedCrossRefGoogle Scholar
  36. 36.
    Rajagopalan S, Kurz S, Münzel T, et al.: 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 1996, 97:1916–1923. This seminal in vivo study demonstrating a link between angiotensin II, NAD(P)H-oxidase, ROS, and hypertension.PubMedGoogle Scholar
  37. 37.
    Laursen JB, Rajagopalan S, Galis Z, et al.: Role of superoxide in angiotensin II-induced but not catecholamine-induced hypertension. Circulation 1997, 95:588–593.PubMedGoogle Scholar
  38. 38.
    Heitzer T, Wenzel U, Hink U, et al.: Increased NAD(P)H oxidase-mediated superoxide production in renovascular hypertension: evidence for an involvement of protein kinase C. Kidney Int 1999, 55:252–260.PubMedCrossRefGoogle Scholar
  39. 39.
    Dijhorst-Oei LT, Stroes ES, Koomans HA, Rabelink TJ: Acute simultaneous stimulation of nitric oxide and oxygen radicals by angiotensin II in humans in vivo. J Cardiovasc Pharmacol 1999, 33:420–424. This is the first data to show that in healthy humans, angiotensin II infusion reactive oxygen species.CrossRefGoogle Scholar
  40. 40.
    Fukui T, Ishizaka N, Rajagopalan S, et al.: p22phox mRNA expression and NADPH oxidase activity are increased in aortas from hypertensive rats. Cir Res 1997, 80:45–51.Google Scholar
  41. 41.
    Pagano PJ, Chanock SJ, Siwik DA, et al.: Angiotensin II induces p67phox mRNA expression and NADPH oxidase superoxide generation in rabbit aortic adventitial fibroblasts. Hypertension 1998, 32:331–337. This study shows the potential mechanism of how angiotensin II could increase NAD(P)H-oxidase activity.PubMedGoogle Scholar
  42. 42.
    Cooke JP, Dzau VJ: Nitric oxide synthases, role in the genesis of vascular disease. Annu Rev Med 1997, 48:489–509.PubMedCrossRefGoogle Scholar
  43. 43.
    Munzel T, Savegh H, Freeman BA, et al.: Evidence for enhanced vascular superoxide anion production in nitrate tolerance. A novel mechanism underlying tolerance and cross-tolerance. J Clin Invest 1995, 95:187–194.PubMedCrossRefGoogle Scholar
  44. 44.
    Wolf G, Ziyadeh FN, Schroeder R, Stahl RAK: Angiotensin II inhibits inducible nitric oxide synthase in tubular MCT cells by a posttranscriptional mechanism. J Am Soc Nephrol 1997, 8:551–557.PubMedGoogle Scholar
  45. 45.
    Fukai T, Siegfried MR, Ushio-Fukai M, et al.: Modulation of extracellular superoxide dismutase expression by angiotensin II and hypertension. Cir Res 1999, 85:23–28. This study demonstrates that extracellular superoxide dismutase may modulate angiotensin II-induced ROS and could be protective.Google Scholar
  46. 46.
    Vaziri ND, Oveisi F, Ding Y: Role of increased oxygen free radical activity in the pathogenesis of uremic hypertension. Kidney Int 1998, 53:1748–1754.PubMedCrossRefGoogle Scholar
  47. 47.
    Kumar KV, Das UN: Are free radicals involved in the pathobiology of human essential hypertension? Free Radic Res Commun 1993, 19:59–66.PubMedGoogle Scholar
  48. 48.
    Warnholtz A, Nickening G, Schulz E, et al.: Increased NADHoxidase-mediated superoxide production in the early stages of atherosclerosis. Evidence for involvement of the renin-angiotensin system. Circulation 1999, 99:2027–2033.PubMedGoogle Scholar
  49. 49.
    Galle J, Heermeier K: Angiotensin II and oxidized LDL: an unholy alliance creating oxidative stress. Nephrol Dial Transplant 1999, 14:2585–2589. This is a nice review discussing the relationship between angiotensin II and the oxidation of lipoproteins.PubMedCrossRefGoogle Scholar
  50. 50.
    Hansson L, Lindholm LH, Niskanen L, et al.: Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) radomised trial. Lancet 1999, 353:611–616.PubMedCrossRefGoogle Scholar
  51. 51.
    Hansson L, Lindholm LH, Ekbom T, et al.: Radomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity in the Swedish Trial in Old Patients with Hypertension-2 study. Lancet 1999, 354:1751–1756.PubMedCrossRefGoogle Scholar
  52. 52.
    Pitt B, Zannad F, Remme WJ, et al.: The effect of spirolactone on morbidity and mortality in patients with severe heart failure. N Eng J Med 1999, 341:709–717.CrossRefGoogle Scholar

Copyright information

© Current Science Inc. 2000

Authors and Affiliations

  • Gunter Wolf
    • 1
  1. 1.Department of Medicine, Division of Nephrology and OsteologyUniversity of Hamburg, University Hospital EppendorfGermany

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