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Reactive oxygen species in the neuropathogenesis of hypertension

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Abstract

New evidence that has emerged during the past several years clearly demonstrates that reactive oxygen species (ROS) in the brain play a crucial role in blood pressure regulation by serving as signaling molecules within neurons of cardiovascular control regions. In the forebrain, midbrain, and hindbrain, a key role for oxidant stress in the pathogenesis of angiotensin II-dependent and various other models of neurogenic hypertension has also been uncovered. As in the peripheral vasculature, NAD(P)H oxidase appears to be a major enzymatic source of brain ROS, and various homologues of the catalytic subunit of this enzyme appear to be differentially localized to cardiovascular-regulating nuclei in the brain. Recent studies have begun to elucidate the downstream effects of ROS in neurons, and it is now clear that ROS may interact with a number of well-described intracellular signaling pathways involved in neuronal activation. These exciting new discoveries have furthered our understanding of the pathogenesis of neurogenic hypertension and may ultimately lead to the development of new treatments. In this review, we discuss recent evidence in support of a role for brain ROS in the pathogenesis of hypertension and summarize current studies aimed at uncovering the complex mechanisms by which brain ROS regulate blood pressure in both health and cardiovascular disease.

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References and Recommended Reading

  1. Fitzsimons J: Angiotensin stimulation of the central nervous system. Rev Physiol Biochem Pharmacol 1980, 87:117–167.

    PubMed  CAS  Google Scholar 

  2. Simpson JB: The circumventricular organs and the central actions of angiotensin. Neuroendocrinology 1981, 32:248–256.

    PubMed  CAS  Google Scholar 

  3. Chapleau MW, Abboud FM: Neuro-cardiovascular regulation: from molecules to man. Introduction. Ann NY Acad Sci 2001, 940:xiii-xxii.

    Article  PubMed  CAS  Google Scholar 

  4. Esler M, Kaye D: Sympathetic nervous system activation in essential hypertension, cardiac failure and psychosomatic heart disease. J Cardiovasc Pharmacol 2000, 35:S1-S7.

    Article  PubMed  CAS  Google Scholar 

  5. Rahmouni K, Correia ML, Haynes WG, Mark AL: Obesityassociated hypertension: new insights into mechanisms. Hypertension 2005, 45:9–14.

    Article  PubMed  CAS  Google Scholar 

  6. Felder RB, Francis J, Zhang ZH, et al.: Heart failure and the brain: new perspectives. Am J Physiol Regul Integr Comp Physiol 2003, 284:R259-R276.

    PubMed  CAS  Google Scholar 

  7. Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW: Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res 1994, 74:1141–1148. This groundbreaking paper was the first to demonstrate the presence of tissue NAD(P)H oxidase, and it initiated the field of research dedicated to the role of oxidative stress in the pathogenesis of hypertension.

    PubMed  CAS  Google Scholar 

  8. Zimmerman MC, Davisson RL: Redox signaling in central neural regulation of cardiovascular function. Prog Biophys Mol Biol 2004, 84:125–149.

    Article  PubMed  CAS  Google Scholar 

  9. Buggy J, Fink GD, Johnson AK, Brody MJ: Prevention of the development of renal hypertension by anteroventral third ventricular tissue lesions. Circ Res 1977, 40:I110-I117.

    PubMed  CAS  Google Scholar 

  10. Collister JP, Hendel MD: Chronic effects of angiotensin II and AT1 receptor antagonists in subfornical organ-lesioned rats. Clin Exper Pharmacol Physiol 2005, 32:462–466.

    Article  CAS  Google Scholar 

  11. Zimmerman MC, Lazartigues E, Sharma RV, Davisson RL: Hypertension caused by angiotensin II infusion involves increased superoxide production in the central nervous system. Circ Res 2004, 95:210–216. This study was the first to demonstrate that the hypertension caused by low doses of circulating Ang II depends on the production of superoxide as an intracellular signaling molecule in forebrain circumventricular organs. This study provided the first evidence for oxidative stress in Ang II-induced neurogenic hypertension.

    Article  PubMed  CAS  Google Scholar 

  12. Sakai K, Sigmund CD: Molecular evidence of the tissue renin-angiotensin systems: a focus on the brain. Curr Hypertens Rep 2005, 7:135–140.

    PubMed  CAS  Google Scholar 

  13. Zimmerman MC, Lazartigues E, Lang JA, et al.: Superoxide mediates the actions of angiotensin II in the central nervous system. Circ Res 2002, 91:1038–1045. This pioneering study opened up a whole new area of investigation in neurocardiovascular regulation in health and disease by showing that the physiologic responses to brain angiotensin II involve the production of reactive oxygen species. Using adenoviral-mediated expression of cytoplasmic and mitochondrial SOD, this study conclusively demonstrated a role for SOD in angiotensin II signaling in the brain.

    Article  PubMed  CAS  Google Scholar 

  14. Chan SHH, Hsu K-S, Huang C-C, et al.: NADPH oxidase-derived superoxide anion mediates angiotensin II-induced pressor effect via activation of p38 mitogenactivated protein kinase in the rostral ventrolateral medulla. Circ Res 2005, 97:772–780. Angiotensin II activation of the MAP kinase pathway in neurons is shown to be dependent on superoxide production by an NAD(P)H oxidase in this elegant series of experiments.

    Article  PubMed  CAS  Google Scholar 

  15. Gao L, Wang W, Li Y-L, et al.: Sympathoexcitation by central Ang II: roles for AT1 receptor upregulation and NAD(P)H oxidase in RVLM. Am J Physiol Heart Circ Physiol 2005, 288:H2271-H2279. This is the first study to show that angiotensin II in the brain upregulates the expression of NAD(P)H oxidase subunits in crucial cardiovascular-regulating nuclei. An excellent discussion of the current evidence in support of a role for ROS in central angiotensin II-mediated sympathoexcitation is included.

    Article  PubMed  CAS  Google Scholar 

  16. Campese VM, Shaohua Y, Huiquin Z: Oxidative stress mediates angiotensin II-dependent stimulation of sympathetic nerve activity. Hypertension 2005, 46:533–539.

    Article  PubMed  CAS  Google Scholar 

  17. Lu N, Helwig BG, Fels RJ, et al.: Central Tempol alters basal sympathetic nerve discharge and attenuates sympathetic excitation to central Ang II. Am J Physiol Heart Circ Physiol 2004, 287:H2626-H2633.

    Article  PubMed  CAS  Google Scholar 

  18. Tai M-H, Wang L-L, Wu KLH, Chan JYH: Increased superoxide anion in rostral ventrolateral medulla contributes to hypertension in spontaneously hypertensive rats via interactions with nitric oxide. Free Rad Biol Med 2005, 38:450–462.

    Article  PubMed  CAS  Google Scholar 

  19. Touyz RM: Intracellular mechanisms involved in vascular remodelling of resistance arteries in hypertension: role of angiotensin II. Exp Physiol 2005, 90:449–455.

    Article  PubMed  CAS  Google Scholar 

  20. Touyz RM: Reactive oxygen species, vascular oxidative stress, and redox signaling in hypertension: What is the clinical significance? Hypertension 2004, 44:248–252.

    Article  PubMed  CAS  Google Scholar 

  21. Ohtsu H, Frank GD, Utsunomiya H, Eguchi S: Redoxdependent protein kinase regulation by angiotensin II: mechanistic insights and its pathophysiology. Antioxid Redox Signal 2005, 7:1315–1326.

    Article  PubMed  CAS  Google Scholar 

  22. Griendling KK: Novel NAD(P)H oxidases in the cardiovascular system. Heart 2004, 90:491–493.

    Article  PubMed  CAS  Google Scholar 

  23. Lambeth JD: NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol 2004, 4:181–189. This excellent review details the regulatory steps involved in the activation of NAD(P)H oxidase and includes an informative discussion of the potential targets of superoxide production in nonphagocytic cells.

    Article  PubMed  CAS  Google Scholar 

  24. Infanger DW, Sharma RV, Davisson RL: NADPH oxidases of the brain: distribution, regulation and function. Antioxid Redox Signal 2006, In press.

  25. Infanger DW, Sharma RV, Davisson RL: Differential expression of Nox homologues in cardiovascular (CV) regulatory nuclei of mouse brain. FASEB J 2006, 20:1190A.

    Google Scholar 

  26. Zimmerman MC, Dunlay RP, Lazartigues E, et al.: Requirement for Rac1-dependent NADPH oxidase in the cardiovascular and dipsogenic actions of angiotensin II in the brain. Circ Res 2004, 95:532–539. This study demonstrates a role for the activation of Rac1 in the physiologic responses to brain angiotensin II, and it is the first to implicate NAD(P)H oxidase as a source of angiotensin II-mediated superoxide production in forebrain circumventricular organs.

    Article  PubMed  CAS  Google Scholar 

  27. Wang G, Anrather J, Huang J, et al.: NADPH oxidase contributes to angiotensin II signaling in the nucleus tractus solitarius. J Neurosci 2004, 24:5516–5524. This study was among the first to reveal a potential mechanism by which ROS may impact neuronal activation in cardiovascular-regulating nuclei by demonstrating that angiotensin II-induced superoxide production by an NAD(P)H oxidase enhances calcium currents in neurons of the NTS. Importantly, this study also demonstrated colocalization of the angiotensin II receptor and the NAD(P)H oxidase subunit gp91phox to neuronal processes within the NTS.

    Article  PubMed  CAS  Google Scholar 

  28. Rey FE, Cifuentes ME, Kiarash A, et al.: Novel competitive inhibitor of NAD(P)H oxidase assembly attenuates vascular O2- and systolic blood pressure in mice. Circ Res 2001, 89:408–414.

    PubMed  CAS  Google Scholar 

  29. Sun C, Sellers KW, Sumners C, Raizada MK: NAD(P)H oxidase inhibition attenuates neuronal chronotropic actions of angiotensin II. Circ Res 2005, 96:659–666. Previous work from this group has been instrumental in outlining the intracellular signaling pathways involved in neuronal activation by angiotensin II. This important study implicates a role for ROS in these well-defined pathways by demonstrating that neuronal potassium currents are regulated by an angiotensin II-induced increase in superoxide production by an NAD(P)H oxidase.

    Article  PubMed  CAS  Google Scholar 

  30. Lee MC, Shoji H, Miyazaki H, et al.: Assessment of oxidative stress in the spontaneously hypertensive rat brain using electron spin resonance (ESR) imaging and in vivo L-Band ESR. Hypertens Res 2004, 27:485–492.

    Article  PubMed  CAS  Google Scholar 

  31. Kishi T, Hirooka Y, Kimura Y, et al.: Increased reactive oxygen species in rostral ventrolateral medulla contribute to neural mechanisms of hypertension in stroke-prone spontaneously hypertensive rats. Circulation 2004, 109:2357–2362.

    Article  PubMed  CAS  Google Scholar 

  32. Blume A, Herdegen T, Unger T: Angiotensin peptides and inducible transcription factors. J Mol Med 1999, 77:339–357.

    Article  PubMed  CAS  Google Scholar 

  33. Chan JYH, Wang L-L, Lee H-Y, Chan SHH: Augmented upregulation by c-fos of angiotensin subtype 1 receptor in nucleus tractus solitarii of spontaneously hypertensive rats. Hypertension 2002, 40:335–341.

    Article  PubMed  CAS  Google Scholar 

  34. Hector Polizio A, Pena C: Effects of angiotensin II type 1 receptor blockade on the oxidative stress in spontaneously hypertensive rat tissues. Regul Pept 2005, 128:1–5.

    Article  CAS  Google Scholar 

  35. Sellers KW, Sun C, Diez-Freire C, et al.: Novel mechanism of brain soluble epoxide hydrolase-mediated blood pressure regulation in the spontaneously hypertensive rat. FASEB J 2005, 19:626–628.

    PubMed  CAS  Google Scholar 

  36. Taylor MM, Samson WK: Adrenomedullin and central cardiovascular regulation. Peptides 2001, 22:1803–1807.

    Article  PubMed  CAS  Google Scholar 

  37. Fujita M, Kuwaki T, Ando K, Fujita T: Sympatho-inhibitory action of endogenous adrenomedullin through inhibition of oxidative stress in the brain. Hypertension 2005, 45:1165–1172.

    Article  PubMed  CAS  Google Scholar 

  38. Sumners C, Fleegal MA, Zhu M: Angiotensin AT1 receptor signalling pathways in neurons. Clin Exper Pharmacol Physiol 2002, 29:483–490.

    Article  CAS  Google Scholar 

  39. Zimmerman MC, Sharma RV, Davisson RL: Superoxide mediates angiotensin II-induced influx of extracellular calcium in neural cells. Hypertension 2005, 45:717–723.

    Article  PubMed  CAS  Google Scholar 

  40. Hongpaisan J, Winters CA, Andrews SB: Strong calcium entry activates mitochondrial superoxide generation, upregulating kinase signaling in hippocampal neurons. J Neurosci 2004, 24:10878–10887.

    Article  PubMed  CAS  Google Scholar 

  41. Sun C, Li H, Leng L, et al.: Macrophage migration inhibitory factor: an intracellular inhibitor of angiotensin II-induced increases in neuronal activity. J Neurosci 2004, 24:9944–9952.

    Article  PubMed  CAS  Google Scholar 

  42. Matsuura T, Sun C, Leng L, et al.: Macrophage migration inhibitory factor (MIF) increases neuronal delayed rectifier K+ current. J Neurophysiol 2005, 95:1042–1048.

    Article  PubMed  CAS  Google Scholar 

  43. Turpaev KT: Reactive oxygen species and regulation of gene expression. Biochemistry (Moscow) 2002, 67:281–292.

    Article  CAS  Google Scholar 

  44. Dalton TP, Shertzer HG, Puga A: Regulation of gene expression by reactive oxygen. Ann Rev Pharmacol Toxicol 1999, 39:67–101.

    Article  CAS  Google Scholar 

  45. Daniels D, Yee DK, Faulconbridge LF, Fluharty SJ: Divergent behavioral roles of angiotensin receptor intracellular signaling cascades. Endocrinology 2005, 146:5552–5560.

    Article  PubMed  CAS  Google Scholar 

  46. Fleegal MA, Sumners C: Drinking behavior elicited by central injection of angiotensin II: roles for protein kinase C and Ca2+/calmodulin-dependent protein kinase II. Am J Physiol Regul Integr Comp Physiol 2003, 285:R632-R640.

    PubMed  Google Scholar 

  47. Davisson RL, Oliverio MI, Coffman TM, Sigmund CD: Divergent functions of angiotensin II receptor isoforms in the brain. J Clin Invest 2000, 106:103–106.

    PubMed  CAS  Google Scholar 

  48. Fleegal MA, Sumners C: Angiotensin II induction of AP-1 in neurons requires stimulation of PI3-K and JNK. Biochem Biophys Res Comm 2003, 310:470–477.

    Article  PubMed  CAS  Google Scholar 

  49. Rylski M, Kaczmarek L: AP-1 targets in the brain. Front Biosci 2004, 9:8–23.

    Article  PubMed  CAS  Google Scholar 

  50. Wu S, Gao J, Ohlemeyer C, et al.: Activation of AP-1 through reactive oxygen species by angiotensin II in rat cardiomyocytes. Free Rad Biol Med 2005, 39:1601–1610.

    Article  PubMed  CAS  Google Scholar 

  51. Lindley TE, Doobay MF, Sharma RV, Davisson RL: Superoxide is involved in the central nervous system activation and sympathoexcitation of myocardial infarctioninduced heart failure. Circ Res 2004, 94:402–409.

    Article  PubMed  CAS  Google Scholar 

  52. Contag PR, Olomu IN, Stevenson DK, Contag CH: Bioluminescent indicators in living mammals. Nat Med 1998, 4:245–247.

    Article  PubMed  CAS  Google Scholar 

  53. Leung TH, Hoffmann A, Baltimore D: One nucleotide in a kappaB site can determine cofactor specificity for NFkappaB dimers. Cell 2004, 118:453–464.

    Article  PubMed  CAS  Google Scholar 

  54. Zhang L, Ma Y, Zhang J, et al.: A new cellular signaling mechanism for angiotensin II activation of NF-kappaB: an IkappaB-independent, RSK-mediated phosphorylation of p65. Arterioscler Thromb Vasc Biol 2005, 25:1148–1153.

    Article  PubMed  CAS  Google Scholar 

  55. Brasier AR, Jamaluddin M, Han Y, et al.: Angiotensin II induces gene transcription through cell-type-dependent effects on the nuclear factor-kappaB (NF-kappaB) transcription factor. Mol Cell Biochem 2000, 212:155–169.

    Article  PubMed  CAS  Google Scholar 

  56. Ruiz-Ortega M, Lorenzo O, Ruperez M, et al.: Angiotensin II activates nuclear transcription factor kappaB through AT1 and AT2 in vascular smooth muscle cells: molecular mechanisms. Circ Res 2000, 86:1266–1272.

    PubMed  CAS  Google Scholar 

  57. Zhang L, Cheng J, Ma Y, et al.: Dual pathways for nuclear factor kappaB activation by angiotensin II in vascular smooth muscle: phosphorylation of p65 by IkappaB kinase and ribosomal kinase. Circ Res 2005, 97:975–982.

    Article  PubMed  CAS  Google Scholar 

  58. Sanz-Rosa D, Oubina MP, Cediel E, et al.: Effect of AT1 receptor antagonism on vascular and circulating inflammatory mediators in SHR: role of NF-kappaB/IkappaB system. Am J Physiol Heart Circ Physiol 2005, 288:H11-H15.

    Google Scholar 

  59. Gupta S, Young D, Sen S: Inhibition of NF-kappaB induces regression of cardiac hypertrophy, independent of blood pressure control, in spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 2005, 289:H20-H29.

    Article  PubMed  CAS  Google Scholar 

  60. Rodriguez-Iturbe B, Ferrebuz A, Vanegas V, et al.: Early and sustained inhibition of nuclear factor-kappaB prevents hypertension in spontaneously hypertensive rats. J Pharmacol Exp Ther 2005, 315:51–57.

    Article  PubMed  CAS  Google Scholar 

  61. Mattson MP, Camandola S: NF-kappaB in neuronal plasticity and neurodegenerative disorders. J Clin Invest 2001, 107:247–254.

    Article  PubMed  CAS  Google Scholar 

  62. Meffert MK, Baltimore D: Physiological functions for brain NF-kappaB. Trends Neurosci 2005, 28:37–43.

    Article  PubMed  CAS  Google Scholar 

  63. Ramchandra R, Barrett CJ, Malpas SC: Nitric oxide and sympathetic nerve activity in the control of blood pressure. Clin Exper Pharmacol Physiol 2005, 32:440–446.

    Article  CAS  Google Scholar 

  64. Zucker IH, Liu JL: Angiotensin II—nitric oxide interactions in the control of sympathetic outflow in heart failure. Heart Fail Rev 2000, 5:27–43.

    Article  PubMed  CAS  Google Scholar 

  65. Kimura Y, Hirooka Y, Sagara Y, et al.: Overexpression of inducible nitric oxide synthase in rostral ventrolateral medulla causes hypertension and sympathoexcitation via an increase in oxidative stress. Circ Res 2005, 96:252–260.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Robin L. Davisson PhD.

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Peterson, J.R., Sharma, R.V. & Davisson, R.L. Reactive oxygen species in the neuropathogenesis of hypertension. Current Science Inc 8, 232–241 (2006). https://doi.org/10.1007/s11906-006-0056-1

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