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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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Endothelial function in isolated aortae from Tg and WT mice. a Aortic contraction to a single dose of KCl (80 mM). N = 10. b Dose response curve to phenylephrine (PE; 10−9 to 10−6 M). N = 10. c Endothelial-dependent relaxation to acetylcholine (ACh). N = 10. d Relaxation to sodium nitroprusside (SNP). N = 10. e, f Relaxation to Ach in the presence and absence of AngII (0.1 μM, 30 min) in WT and Tg aorta, respectively. N = 10. *P < 0.05 comparing EC50 and Emax. g, h Relaxation to SNP in WT and Tg, respectively, in the presence and absence of AngII (0.1 μM, 30 min). N = 10. i, j Relaxation to ACh in WT and Tg aortae, respectively, after co-incubation with AngII (0.1 μM, 30 min) and the superoxide scavenger, tiron (10 mM). N = 3, P = NS
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Fig4: Endothelial function in isolated aortae from Tg and WT mice. a Aortic contraction to a single dose of KCl (80 mM). N = 10. b Dose response curve to phenylephrine (PE; 10−9 to 10−6 M). N = 10. c Endothelial-dependent relaxation to acetylcholine (ACh). N = 10. d Relaxation to sodium nitroprusside (SNP). N = 10. e, f Relaxation to Ach in the presence and absence of AngII (0.1 μM, 30 min) in WT and Tg aorta, respectively. N = 10. *P < 0.05 comparing EC50 and Emax. g, h Relaxation to SNP in WT and Tg, respectively, in the presence and absence of AngII (0.1 μM, 30 min). N = 10. i, j Relaxation to ACh in WT and Tg aortae, respectively, after co-incubation with AngII (0.1 μM, 30 min) and the superoxide scavenger, tiron (10 mM). N = 3, P = NS

Mentions: To determine the effect of increased endothelial Nox2 levels on vasomotor tone, we studied isolated aortic rings from Tg and wild-type littermate mice. Constrictor responses to potassium chloride (80 mM) and phenylephrine were similar between groups (Fig. 4a, b). Endothelium-dependent vasorelaxation to acetylcholine and endothelial-independent relaxation to sodium nitroprusside were both similar in wild-type and Tg groups (Fig. 4c, d). To study vasorelaxation under conditions where Nox2 was activated, aortic rings were stimulated with angiotensin II (1 μM, 30 min) prior to the assessment of dilator responses. A small but significant decrease in the maximum acetylcholine-induced relaxation was observed in angiotensin II-treated wild-type rings compared to saline control when comparing the entire curve but there was no change in EC50 (logEC50: −7.37 ± 0.08 vs. −7.46 ± 0.04 M, respectively, P = ns; n = 10) (Fig. 4e). The angiotensin II-treated Tg group showed a greater reduction in acetylcholine-induced relaxation with a modest but significant rightward shift of the EC50 (logEC50: −7.19 ± 0.05 vs. −7.37 ± 0.05 M, respectively, *P < 0.05; n = 10) (Fig. 4f). Angiotensin II administration had no effect on endothelial-independent relaxation to sodium nitroprusside in either group (Fig. 4g, h). Pre-treatment with the superoxide scavenger, tiron (10 mM) prior to angiotensin II treatment prevented the angiotensin II-induced attenuation of the acetylcholine relaxation in both Wt and Tg aorta (Fig. 4i, j). The level of basal NO formation was assessed by studying the response to the NOS inhibitor, l-NMMA, in lightly pre-constricted aortic rings (30% of phenylephrine maximum). The response in Wt and Tg vessels was found to be similar (3.9 ± 0.7 vs. 3.4 ± 0.6 mN, respectively, P = ns; n = 3).Fig. 4


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)

Endothelial function in isolated aortae from Tg and WT mice. a Aortic contraction to a single dose of KCl (80 mM). N = 10. b Dose response curve to phenylephrine (PE; 10−9 to 10−6 M). N = 10. c Endothelial-dependent relaxation to acetylcholine (ACh). N = 10. d Relaxation to sodium nitroprusside (SNP). N = 10. e, f Relaxation to Ach in the presence and absence of AngII (0.1 μM, 30 min) in WT and Tg aorta, respectively. N = 10. *P < 0.05 comparing EC50 and Emax. g, h Relaxation to SNP in WT and Tg, respectively, in the presence and absence of AngII (0.1 μM, 30 min). N = 10. i, j Relaxation to ACh in WT and Tg aortae, respectively, after co-incubation with AngII (0.1 μM, 30 min) and the superoxide scavenger, tiron (10 mM). N = 3, P = NS
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Fig4: Endothelial function in isolated aortae from Tg and WT mice. a Aortic contraction to a single dose of KCl (80 mM). N = 10. b Dose response curve to phenylephrine (PE; 10−9 to 10−6 M). N = 10. c Endothelial-dependent relaxation to acetylcholine (ACh). N = 10. d Relaxation to sodium nitroprusside (SNP). N = 10. e, f Relaxation to Ach in the presence and absence of AngII (0.1 μM, 30 min) in WT and Tg aorta, respectively. N = 10. *P < 0.05 comparing EC50 and Emax. g, h Relaxation to SNP in WT and Tg, respectively, in the presence and absence of AngII (0.1 μM, 30 min). N = 10. i, j Relaxation to ACh in WT and Tg aortae, respectively, after co-incubation with AngII (0.1 μM, 30 min) and the superoxide scavenger, tiron (10 mM). N = 3, P = NS
Mentions: To determine the effect of increased endothelial Nox2 levels on vasomotor tone, we studied isolated aortic rings from Tg and wild-type littermate mice. Constrictor responses to potassium chloride (80 mM) and phenylephrine were similar between groups (Fig. 4a, b). Endothelium-dependent vasorelaxation to acetylcholine and endothelial-independent relaxation to sodium nitroprusside were both similar in wild-type and Tg groups (Fig. 4c, d). To study vasorelaxation under conditions where Nox2 was activated, aortic rings were stimulated with angiotensin II (1 μM, 30 min) prior to the assessment of dilator responses. A small but significant decrease in the maximum acetylcholine-induced relaxation was observed in angiotensin II-treated wild-type rings compared to saline control when comparing the entire curve but there was no change in EC50 (logEC50: −7.37 ± 0.08 vs. −7.46 ± 0.04 M, respectively, P = ns; n = 10) (Fig. 4e). The angiotensin II-treated Tg group showed a greater reduction in acetylcholine-induced relaxation with a modest but significant rightward shift of the EC50 (logEC50: −7.19 ± 0.05 vs. −7.37 ± 0.05 M, respectively, *P < 0.05; n = 10) (Fig. 4f). Angiotensin II administration had no effect on endothelial-independent relaxation to sodium nitroprusside in either group (Fig. 4g, h). Pre-treatment with the superoxide scavenger, tiron (10 mM) prior to angiotensin II treatment prevented the angiotensin II-induced attenuation of the acetylcholine relaxation in both Wt and Tg aorta (Fig. 4i, j). The level of basal NO formation was assessed by studying the response to the NOS inhibitor, l-NMMA, in lightly pre-constricted aortic rings (30% of phenylephrine maximum). The response in Wt and Tg vessels was found to be similar (3.9 ± 0.7 vs. 3.4 ± 0.6 mN, respectively, P = ns; n = 3).Fig. 4

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