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Role of endothelial Nox2 NADPH oxidase in angiotensin II-induced hypertension and vasomotor dysfunction.

Murdoch CE, Alom-Ruiz SP, Wang M, Zhang M, Walker S, Yu B, Brewer A, Shah AM - Basic Res. Cardiol. (2011)

Bottom Line: Basal NADPH oxidase activity, endothelial function and blood pressure were unaltered in Tg compared to wild-type littermates.Angiotensin II caused a greater increase in ROS production in Tg compared to wild-type aorta and attenuated acetylcholine-induced vasorelaxation.Both low and high dose chronic angiotensin II infusion increased telemetric ambulatory blood pressure more in Tg compared to wild-type, but with different patterns of BP change and aortic remodeling depending upon the dose of angiotensin II dose.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Division, King's College London British Heart Foundation Centre, London, UK.

ABSTRACT
NADPH oxidase (Nox)-derived reactive oxygen species (ROS) are known to be involved in angiotensin II-induced hypertension and endothelial dysfunction. Several Nox isoforms are expressed in the vessel wall, among which Nox2 is especially abundant in the endothelium. Endothelial Nox2 levels rise during hypertension but little is known about the cell-specific role of endothelial Nox2 in vivo. To address this question, we generated transgenic mice with endothelial-specific overexpression of Nox2 (Tg) and studied the effects on endothelial function and blood pressure. Tg had an about twofold increase in endothelial Nox2 levels which was accompanied by an increase in p22phox levels but no change in levels of other Nox isoforms or endothelial nitric oxide synthase (eNOS). Basal NADPH oxidase activity, endothelial function and blood pressure were unaltered in Tg compared to wild-type littermates. Angiotensin II caused a greater increase in ROS production in Tg compared to wild-type aorta and attenuated acetylcholine-induced vasorelaxation. Both low and high dose chronic angiotensin II infusion increased telemetric ambulatory blood pressure more in Tg compared to wild-type, but with different patterns of BP change and aortic remodeling depending upon the dose of angiotensin II dose. These results indicate that an increase in endothelial Nox2 levels contributes to angiotensin II-induced endothelial dysfunction, vascular remodeling and hypertension.

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Immunostaining for Nox2. Aortic sections stained for Nox2 (green) and CD31 (red) as an endothelial marker. The yellowcolour in the merged images in the bottom panels denotes co-localization. Scale bars 50 μm
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Fig2: Immunostaining for Nox2. Aortic sections stained for Nox2 (green) and CD31 (red) as an endothelial marker. The yellowcolour in the merged images in the bottom panels denotes co-localization. Scale bars 50 μm

Mentions: Two independent lines of endothelium-targeted Nox2-overexpressing mice on a C57/Bl6 background were generated. The lines were similar and data presented herein are from line 1. Tg and WT mice were obtained in the predicted Mendelian ratio and there were no differences in gross morphology or in body and organ weights between genotypes (Online Resource 1). The level of Nox2 protein was significantly increased (twofold) in Tg aorta compared to wild-type (Fig. 1a) and was similarly increased in Tg line 2 (Online Resource 2A). Isolated cultured coronary microvascular endothelial cells (CMEC) of Tg also had a twofold increase in Nox2 levels compared to wild-type CMEC (Fig. 1b). Mechanical denudation of the endothelium from aortic segments reduced Nox2 proteins levels in both Tg and wild-type groups and abolished the difference between groups (Fig. 1c), indicating that the increase in Nox2 derived from the endothelium. The endothelial-specificity of Nox2 overexpression was further confirmed by immunostaining sections of aorta, where an increase in Nox2 that co-localized with an endothelial marker, CD31, was observed in Tg (Fig. 2).Fig. 1


Role of endothelial Nox2 NADPH oxidase in angiotensin II-induced hypertension and vasomotor dysfunction.

Murdoch CE, Alom-Ruiz SP, Wang M, Zhang M, Walker S, Yu B, Brewer A, Shah AM - Basic Res. Cardiol. (2011)

Immunostaining for Nox2. Aortic sections stained for Nox2 (green) and CD31 (red) as an endothelial marker. The yellowcolour in the merged images in the bottom panels denotes co-localization. Scale bars 50 μm
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3105229&req=5

Fig2: Immunostaining for Nox2. Aortic sections stained for Nox2 (green) and CD31 (red) as an endothelial marker. The yellowcolour in the merged images in the bottom panels denotes co-localization. Scale bars 50 μm
Mentions: Two independent lines of endothelium-targeted Nox2-overexpressing mice on a C57/Bl6 background were generated. The lines were similar and data presented herein are from line 1. Tg and WT mice were obtained in the predicted Mendelian ratio and there were no differences in gross morphology or in body and organ weights between genotypes (Online Resource 1). The level of Nox2 protein was significantly increased (twofold) in Tg aorta compared to wild-type (Fig. 1a) and was similarly increased in Tg line 2 (Online Resource 2A). Isolated cultured coronary microvascular endothelial cells (CMEC) of Tg also had a twofold increase in Nox2 levels compared to wild-type CMEC (Fig. 1b). Mechanical denudation of the endothelium from aortic segments reduced Nox2 proteins levels in both Tg and wild-type groups and abolished the difference between groups (Fig. 1c), indicating that the increase in Nox2 derived from the endothelium. The endothelial-specificity of Nox2 overexpression was further confirmed by immunostaining sections of aorta, where an increase in Nox2 that co-localized with an endothelial marker, CD31, was observed in Tg (Fig. 2).Fig. 1

Bottom Line: Basal NADPH oxidase activity, endothelial function and blood pressure were unaltered in Tg compared to wild-type littermates.Angiotensin II caused a greater increase in ROS production in Tg compared to wild-type aorta and attenuated acetylcholine-induced vasorelaxation.Both low and high dose chronic angiotensin II infusion increased telemetric ambulatory blood pressure more in Tg compared to wild-type, but with different patterns of BP change and aortic remodeling depending upon the dose of angiotensin II dose.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Division, King's College London British Heart Foundation Centre, London, UK.

ABSTRACT
NADPH oxidase (Nox)-derived reactive oxygen species (ROS) are known to be involved in angiotensin II-induced hypertension and endothelial dysfunction. Several Nox isoforms are expressed in the vessel wall, among which Nox2 is especially abundant in the endothelium. Endothelial Nox2 levels rise during hypertension but little is known about the cell-specific role of endothelial Nox2 in vivo. To address this question, we generated transgenic mice with endothelial-specific overexpression of Nox2 (Tg) and studied the effects on endothelial function and blood pressure. Tg had an about twofold increase in endothelial Nox2 levels which was accompanied by an increase in p22phox levels but no change in levels of other Nox isoforms or endothelial nitric oxide synthase (eNOS). Basal NADPH oxidase activity, endothelial function and blood pressure were unaltered in Tg compared to wild-type littermates. Angiotensin II caused a greater increase in ROS production in Tg compared to wild-type aorta and attenuated acetylcholine-induced vasorelaxation. Both low and high dose chronic angiotensin II infusion increased telemetric ambulatory blood pressure more in Tg compared to wild-type, but with different patterns of BP change and aortic remodeling depending upon the dose of angiotensin II dose. These results indicate that an increase in endothelial Nox2 levels contributes to angiotensin II-induced endothelial dysfunction, vascular remodeling and hypertension.

Show MeSH
Related in: MedlinePlus