Role of NADH/NADPH oxidase-derived H2O2 in angiotensin II-induced vascular hypertrophy

A. Maziar Zafari, Masuko Ushio-Fukai, Marjorie Akers, Qiqin Yin, Aalok Shah, David G. Harrison, W. Robert Taylor, Kathy K. Griendling

Research output: Contribution to journalArticle

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Abstract

Recent evidence suggests that oxidative mechanisms may be involved in vascular smooth muscle cell (VSMC) hypertrophy. We previously showed that angiotensin II (Ang II) increases superoxide production by activating an NADH/NADPH oxidase, which contributes to hypertrophy. In this study, we determined whether Ang II stimulation of this oxidase results in H2O2 production by studying the effects of Ang II on intracellular H2O2 generation, intracellular superoxide dismutase and catalase activity, and hypertrophy. Ang II (100 nmol/L) significantly increased intracellular H2O2 levels at 4 hours. Neither superoxide dismutase activity nor catalase activity was affected by Ang II; the SOD present in VSMCs is sufficient to metabolize Ang II-stimulated superoxide to H2O2, which accumulates more rapidly than it is degraded by catalase. This increase in H2O2 was inhibited by extracellular catalase, diphenylene iodonium, an inhibitor of the NADH/NADPH oxidase, and the AT1 receptor blocker losartan. In VSMCs stably transfected with antisense p22phox, a critical component of the NADH/NADPH oxidase in which oxidase activity was markedly reduced, Ang II- induced production of H2O2 was almost completely inhibited, confirming that the source of Ang II-induced H2O2 was the NADH/NADPH oxidase. Using a novel cell line that stably overexpresses catalase, we showed that this increased H2O2 is a critical step in VSMC hypertrophy, a hallmark of many vascular diseases. Inhibition of intracellular superoxide dismutase by diethylthiocarbamate (1 mmol/L) also resulted in attenuation of Ang II- induced hypertrophy (62±2% inhibition). These data indicate that AT1 receptor-mediated production of superoxide generated by the NADH/NADPH oxidase is followed by an increase in intracellular H2O2, suggesting a specific role for these oxygen species and scavenging systems in modifying the intracellular redox state in vascular growth.

Original languageEnglish (US)
Pages (from-to)488-495
Number of pages8
JournalHypertension
Volume32
Issue number3
DOIs
StatePublished - Sep 1998

Fingerprint

NADPH Oxidase
Angiotensin II
Hypertrophy
Blood Vessels
Catalase
Superoxides
Superoxide Dismutase
Vascular Smooth Muscle
Smooth Muscle Myocytes
Oxidoreductases
NADH oxidase
Losartan
Vascular Diseases
Oxidation-Reduction
Oxygen
Cell Line
Growth

Keywords

  • Angiotensin II
  • Catalase
  • Hydrogen peroxide
  • Hypertrophy
  • NADH
  • NADPH oxidase
  • Superoxide dismutase
  • Vascular smooth muscle

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Zafari, A. M., Ushio-Fukai, M., Akers, M., Yin, Q., Shah, A., Harrison, D. G., ... Griendling, K. K. (1998). Role of NADH/NADPH oxidase-derived H2O2 in angiotensin II-induced vascular hypertrophy. Hypertension, 32(3), 488-495. https://doi.org/10.1161/01.HYP.32.3.488

Role of NADH/NADPH oxidase-derived H2O2 in angiotensin II-induced vascular hypertrophy. / Zafari, A. Maziar; Ushio-Fukai, Masuko; Akers, Marjorie; Yin, Qiqin; Shah, Aalok; Harrison, David G.; Taylor, W. Robert; Griendling, Kathy K.

In: Hypertension, Vol. 32, No. 3, 09.1998, p. 488-495.

Research output: Contribution to journalArticle

Zafari, AM, Ushio-Fukai, M, Akers, M, Yin, Q, Shah, A, Harrison, DG, Taylor, WR & Griendling, KK 1998, 'Role of NADH/NADPH oxidase-derived H2O2 in angiotensin II-induced vascular hypertrophy', Hypertension, vol. 32, no. 3, pp. 488-495. https://doi.org/10.1161/01.HYP.32.3.488
Zafari, A. Maziar ; Ushio-Fukai, Masuko ; Akers, Marjorie ; Yin, Qiqin ; Shah, Aalok ; Harrison, David G. ; Taylor, W. Robert ; Griendling, Kathy K. / Role of NADH/NADPH oxidase-derived H2O2 in angiotensin II-induced vascular hypertrophy. In: Hypertension. 1998 ; Vol. 32, No. 3. pp. 488-495.
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AB - Recent evidence suggests that oxidative mechanisms may be involved in vascular smooth muscle cell (VSMC) hypertrophy. We previously showed that angiotensin II (Ang II) increases superoxide production by activating an NADH/NADPH oxidase, which contributes to hypertrophy. In this study, we determined whether Ang II stimulation of this oxidase results in H2O2 production by studying the effects of Ang II on intracellular H2O2 generation, intracellular superoxide dismutase and catalase activity, and hypertrophy. Ang II (100 nmol/L) significantly increased intracellular H2O2 levels at 4 hours. Neither superoxide dismutase activity nor catalase activity was affected by Ang II; the SOD present in VSMCs is sufficient to metabolize Ang II-stimulated superoxide to H2O2, which accumulates more rapidly than it is degraded by catalase. This increase in H2O2 was inhibited by extracellular catalase, diphenylene iodonium, an inhibitor of the NADH/NADPH oxidase, and the AT1 receptor blocker losartan. In VSMCs stably transfected with antisense p22phox, a critical component of the NADH/NADPH oxidase in which oxidase activity was markedly reduced, Ang II- induced production of H2O2 was almost completely inhibited, confirming that the source of Ang II-induced H2O2 was the NADH/NADPH oxidase. Using a novel cell line that stably overexpresses catalase, we showed that this increased H2O2 is a critical step in VSMC hypertrophy, a hallmark of many vascular diseases. Inhibition of intracellular superoxide dismutase by diethylthiocarbamate (1 mmol/L) also resulted in attenuation of Ang II- induced hypertrophy (62±2% inhibition). These data indicate that AT1 receptor-mediated production of superoxide generated by the NADH/NADPH oxidase is followed by an increase in intracellular H2O2, suggesting a specific role for these oxygen species and scavenging systems in modifying the intracellular redox state in vascular growth.

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