Mitochondria-derived reactive oxygen species mediate sympathoexcitation induced by angiotensin II in the rostral ventrolateral medulla

Masatsugu Nozoe, Yoshitaka Hirooka, Yasuaki Koga, Shuichiro Araki, Satomi Konno, Takuya Kishi, Tomomi Ide, Kenji Sunagawa

Research output: Contribution to journalArticle

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Abstract

OBJECTIVES: Reactive oxygen species (ROS) in the central nervous system are thought to contribute to sympathoexcitation in cardiovascular diseases such as hypertension and heart failure. Nicotinamide adenine dinucleotide phosphate oxidase is a major source of ROS in the central nervous system, which acts as a key mediator (mediators) of angiotensin II (AngII). It is not clear, however, whether mitochondria-derived ROS in the central nervous system also participate in sympathoexcitation. METHODS: In an in-vivo study, we investigated whether the AngII-elicited pressor response in the rostral ventrolateral medulla, which controls sympathetic nerve activity, is attenuated by adenovirus-mediated gene transfer of a mitochondria-derived antioxidant (Mn-SOD). In an in-vitro study, using differentiated PC-12 cells with characteristics similar to those of sympathetic neurons, we examined whether AngII increases mitochondrial ROS production. RESULTS: Overexpression of Mn-SOD attenuated the AngII-induced pressor response and also suppressed AngII-induced ROS production, as evaluated by microdialysis in the rostral ventrolateral medulla. Using reduced MitoTracker red, we showed that AngII increased mitochondrial ROS production in differentiated PC-12 cells in vitro. Overexpression of Mn-SOD and rotenone, a mitochondrial respiratory complex I inhibitor, suppressed AngII-induced ROS production. Depletion of extracellular Ca with ethylene glycol bis-N,N,N′,N′-tetraacetate (EGTA) and administration of p-trifluoromethoxycarbonylcyanide phenylhydrazone, which prevents further Ca uptake into the mitochondria, blocked AngII-elicited mitochondrial ROS production. CONCLUSION: These results indicate that AngII increases the intracellular Ca concentration and that the increase in mitochondrial Ca uptake leads to mitochondrial ROS production.

Original languageEnglish
Pages (from-to)2176-2184
Number of pages9
JournalJournal of hypertension
Volume26
Issue number11
DOIs
Publication statusPublished - Nov 1 2008

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Angiotensin II
Reactive Oxygen Species
Mitochondria
Superoxide Dismutase
Central Nervous System
Electron Transport Complex I
Rotenone
Ethylene Glycol
Egtazic Acid
Microdialysis
NADP
Adenoviridae
Oxidoreductases
Cardiovascular Diseases
Heart Failure
Antioxidants
Hypertension
Neurons
Genes

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Mitochondria-derived reactive oxygen species mediate sympathoexcitation induced by angiotensin II in the rostral ventrolateral medulla. / Nozoe, Masatsugu; Hirooka, Yoshitaka; Koga, Yasuaki; Araki, Shuichiro; Konno, Satomi; Kishi, Takuya; Ide, Tomomi; Sunagawa, Kenji.

In: Journal of hypertension, Vol. 26, No. 11, 01.11.2008, p. 2176-2184.

Research output: Contribution to journalArticle

Nozoe, Masatsugu ; Hirooka, Yoshitaka ; Koga, Yasuaki ; Araki, Shuichiro ; Konno, Satomi ; Kishi, Takuya ; Ide, Tomomi ; Sunagawa, Kenji. / Mitochondria-derived reactive oxygen species mediate sympathoexcitation induced by angiotensin II in the rostral ventrolateral medulla. In: Journal of hypertension. 2008 ; Vol. 26, No. 11. pp. 2176-2184.
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abstract = "OBJECTIVES: Reactive oxygen species (ROS) in the central nervous system are thought to contribute to sympathoexcitation in cardiovascular diseases such as hypertension and heart failure. Nicotinamide adenine dinucleotide phosphate oxidase is a major source of ROS in the central nervous system, which acts as a key mediator (mediators) of angiotensin II (AngII). It is not clear, however, whether mitochondria-derived ROS in the central nervous system also participate in sympathoexcitation. METHODS: In an in-vivo study, we investigated whether the AngII-elicited pressor response in the rostral ventrolateral medulla, which controls sympathetic nerve activity, is attenuated by adenovirus-mediated gene transfer of a mitochondria-derived antioxidant (Mn-SOD). In an in-vitro study, using differentiated PC-12 cells with characteristics similar to those of sympathetic neurons, we examined whether AngII increases mitochondrial ROS production. RESULTS: Overexpression of Mn-SOD attenuated the AngII-induced pressor response and also suppressed AngII-induced ROS production, as evaluated by microdialysis in the rostral ventrolateral medulla. Using reduced MitoTracker red, we showed that AngII increased mitochondrial ROS production in differentiated PC-12 cells in vitro. Overexpression of Mn-SOD and rotenone, a mitochondrial respiratory complex I inhibitor, suppressed AngII-induced ROS production. Depletion of extracellular Ca with ethylene glycol bis-N,N,N′,N′-tetraacetate (EGTA) and administration of p-trifluoromethoxycarbonylcyanide phenylhydrazone, which prevents further Ca uptake into the mitochondria, blocked AngII-elicited mitochondrial ROS production. CONCLUSION: These results indicate that AngII increases the intracellular Ca concentration and that the increase in mitochondrial Ca uptake leads to mitochondrial ROS production.",
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T1 - Mitochondria-derived reactive oxygen species mediate sympathoexcitation induced by angiotensin II in the rostral ventrolateral medulla

AU - Nozoe, Masatsugu

AU - Hirooka, Yoshitaka

AU - Koga, Yasuaki

AU - Araki, Shuichiro

AU - Konno, Satomi

AU - Kishi, Takuya

AU - Ide, Tomomi

AU - Sunagawa, Kenji

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N2 - OBJECTIVES: Reactive oxygen species (ROS) in the central nervous system are thought to contribute to sympathoexcitation in cardiovascular diseases such as hypertension and heart failure. Nicotinamide adenine dinucleotide phosphate oxidase is a major source of ROS in the central nervous system, which acts as a key mediator (mediators) of angiotensin II (AngII). It is not clear, however, whether mitochondria-derived ROS in the central nervous system also participate in sympathoexcitation. METHODS: In an in-vivo study, we investigated whether the AngII-elicited pressor response in the rostral ventrolateral medulla, which controls sympathetic nerve activity, is attenuated by adenovirus-mediated gene transfer of a mitochondria-derived antioxidant (Mn-SOD). In an in-vitro study, using differentiated PC-12 cells with characteristics similar to those of sympathetic neurons, we examined whether AngII increases mitochondrial ROS production. RESULTS: Overexpression of Mn-SOD attenuated the AngII-induced pressor response and also suppressed AngII-induced ROS production, as evaluated by microdialysis in the rostral ventrolateral medulla. Using reduced MitoTracker red, we showed that AngII increased mitochondrial ROS production in differentiated PC-12 cells in vitro. Overexpression of Mn-SOD and rotenone, a mitochondrial respiratory complex I inhibitor, suppressed AngII-induced ROS production. Depletion of extracellular Ca with ethylene glycol bis-N,N,N′,N′-tetraacetate (EGTA) and administration of p-trifluoromethoxycarbonylcyanide phenylhydrazone, which prevents further Ca uptake into the mitochondria, blocked AngII-elicited mitochondrial ROS production. CONCLUSION: These results indicate that AngII increases the intracellular Ca concentration and that the increase in mitochondrial Ca uptake leads to mitochondrial ROS production.

AB - OBJECTIVES: Reactive oxygen species (ROS) in the central nervous system are thought to contribute to sympathoexcitation in cardiovascular diseases such as hypertension and heart failure. Nicotinamide adenine dinucleotide phosphate oxidase is a major source of ROS in the central nervous system, which acts as a key mediator (mediators) of angiotensin II (AngII). It is not clear, however, whether mitochondria-derived ROS in the central nervous system also participate in sympathoexcitation. METHODS: In an in-vivo study, we investigated whether the AngII-elicited pressor response in the rostral ventrolateral medulla, which controls sympathetic nerve activity, is attenuated by adenovirus-mediated gene transfer of a mitochondria-derived antioxidant (Mn-SOD). In an in-vitro study, using differentiated PC-12 cells with characteristics similar to those of sympathetic neurons, we examined whether AngII increases mitochondrial ROS production. RESULTS: Overexpression of Mn-SOD attenuated the AngII-induced pressor response and also suppressed AngII-induced ROS production, as evaluated by microdialysis in the rostral ventrolateral medulla. Using reduced MitoTracker red, we showed that AngII increased mitochondrial ROS production in differentiated PC-12 cells in vitro. Overexpression of Mn-SOD and rotenone, a mitochondrial respiratory complex I inhibitor, suppressed AngII-induced ROS production. Depletion of extracellular Ca with ethylene glycol bis-N,N,N′,N′-tetraacetate (EGTA) and administration of p-trifluoromethoxycarbonylcyanide phenylhydrazone, which prevents further Ca uptake into the mitochondria, blocked AngII-elicited mitochondrial ROS production. CONCLUSION: These results indicate that AngII increases the intracellular Ca concentration and that the increase in mitochondrial Ca uptake leads to mitochondrial ROS production.

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