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Opposing roles of p47phox in basal versus angiotensin II-stimulated alterations in vascular O2- production, vascular tone, and mitogen-activated protein kinase activation.
Circulation. 2004 Mar 16; 109(10):1307-13.Circ

Abstract

BACKGROUND

NADPH oxidase is a major source of vascular superoxide (O2-) production and is implicated in angiotensin II (Ang II)-induced oxidant stress. The p47phox subunit plays an important role in Ang II-induced oxidase activation, but its role in basal oxidase activity and vascular function is unclear.

METHODS AND RESULTS

Aortae from p47phox-/- and matched wild-type (WT) mice (n=9/group) were incubated ex vivo with or without Ang II (200 nmol/L, 30 minutes) and then examined for (1) NADPH-dependent O2- production, (2) endothelium-dependent and -independent vascular relaxation, and (3) activation of mitogen-activated protein kinases (MAPKs). In the absence of Ang II, p47phox-/- vessels had slightly but significantly higher (1.3+/-0.1-fold; P<0.05) NADPH-dependent O2- production than WT; impaired relaxation to acetylcholine (maximum 54+/-4% versus 80+/-3%; P<0.05), which was normalized to WT levels by the O2- scavenger tiron or by Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride, and increased basal phosphorylation of ERK1/2, p38MAPK, and JNK compared with WT. In WT aortae, Ang II increased NADPH-dependent O2- production (2.5+/-0.5-fold; P<0.05), impaired relaxation to acetylcholine (maximum 60+/-6% versus 80+/-3%; P<0.05), and increased ERK1/2, p38MAPK, and JNK phosphorylation (P<0.05). In contrast, Ang II failed to increase O2- production, impair acetylcholine responses, or increase MAPK activation in p47phox-/- aortae.

CONCLUSIONS

p47phox plays a complex dual role in the vasculature. It inhibits basal NADPH oxidase activity but is critical for Ang II-induced vascular dysfunction via activation of NADPH oxidase.

Authors+Show Affiliations

Department of Cardiology, Guy's, King's, and St Thomas' School of Medicine, King's College London, London, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

14993144

Citation

Li, Jian-Mei, et al. "Opposing Roles of P47phox in Basal Versus Angiotensin II-stimulated Alterations in Vascular O2- Production, Vascular Tone, and Mitogen-activated Protein Kinase Activation." Circulation, vol. 109, no. 10, 2004, pp. 1307-13.
Li JM, Wheatcroft S, Fan LM, et al. Opposing roles of p47phox in basal versus angiotensin II-stimulated alterations in vascular O2- production, vascular tone, and mitogen-activated protein kinase activation. Circulation. 2004;109(10):1307-13.
Li, J. M., Wheatcroft, S., Fan, L. M., Kearney, M. T., & Shah, A. M. (2004). Opposing roles of p47phox in basal versus angiotensin II-stimulated alterations in vascular O2- production, vascular tone, and mitogen-activated protein kinase activation. Circulation, 109(10), 1307-13.
Li JM, et al. Opposing Roles of P47phox in Basal Versus Angiotensin II-stimulated Alterations in Vascular O2- Production, Vascular Tone, and Mitogen-activated Protein Kinase Activation. Circulation. 2004 Mar 16;109(10):1307-13. PubMed PMID: 14993144.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Opposing roles of p47phox in basal versus angiotensin II-stimulated alterations in vascular O2- production, vascular tone, and mitogen-activated protein kinase activation. AU - Li,Jian-Mei, AU - Wheatcroft,Stephen, AU - Fan,Lampson M, AU - Kearney,Mark T, AU - Shah,Ajay M, Y1 - 2004/03/01/ PY - 2004/3/3/pubmed PY - 2004/6/29/medline PY - 2004/3/3/entrez SP - 1307 EP - 13 JF - Circulation JO - Circulation VL - 109 IS - 10 N2 - BACKGROUND: NADPH oxidase is a major source of vascular superoxide (O2-) production and is implicated in angiotensin II (Ang II)-induced oxidant stress. The p47phox subunit plays an important role in Ang II-induced oxidase activation, but its role in basal oxidase activity and vascular function is unclear. METHODS AND RESULTS: Aortae from p47phox-/- and matched wild-type (WT) mice (n=9/group) were incubated ex vivo with or without Ang II (200 nmol/L, 30 minutes) and then examined for (1) NADPH-dependent O2- production, (2) endothelium-dependent and -independent vascular relaxation, and (3) activation of mitogen-activated protein kinases (MAPKs). In the absence of Ang II, p47phox-/- vessels had slightly but significantly higher (1.3+/-0.1-fold; P<0.05) NADPH-dependent O2- production than WT; impaired relaxation to acetylcholine (maximum 54+/-4% versus 80+/-3%; P<0.05), which was normalized to WT levels by the O2- scavenger tiron or by Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride, and increased basal phosphorylation of ERK1/2, p38MAPK, and JNK compared with WT. In WT aortae, Ang II increased NADPH-dependent O2- production (2.5+/-0.5-fold; P<0.05), impaired relaxation to acetylcholine (maximum 60+/-6% versus 80+/-3%; P<0.05), and increased ERK1/2, p38MAPK, and JNK phosphorylation (P<0.05). In contrast, Ang II failed to increase O2- production, impair acetylcholine responses, or increase MAPK activation in p47phox-/- aortae. CONCLUSIONS: p47phox plays a complex dual role in the vasculature. It inhibits basal NADPH oxidase activity but is critical for Ang II-induced vascular dysfunction via activation of NADPH oxidase. SN - 1524-4539 UR - https://www.unboundmedicine.com/medline/citation/14993144/Opposing_roles_of_p47phox_in_basal_versus_angiotensin_II_stimulated_alterations_in_vascular_O2__production_vascular_tone_and_mitogen_activated_protein_kinase_activation_ L2 - https://www.ahajournals.org/doi/10.1161/01.CIR.0000118463.23388.B9?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -