Downregulation of Nuclear Factor Erythroid 2–Related Factor and Associated Antioxidant Genes Contributes to Redox-Sensitive Vascular Dysfunction in Hypertension

Lopes, R. A.; Neves, Karla B; Tostes, Rita C.; Montezano, Augusto C; Touyz, Rhian M.

doi:10.1161/hypertensionaha.115.06163

Cited by 114 publications

(81 citation statements)

References 39 publications

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“…This is likely to have occurred through nuclear localization of Nrf2 and binding to the ARE in the promoter regions of Nrf2‐responsive genes 9. Although the effect of AngII on Nrf2 signalling was not investigated in this study, AngII has been shown to elicit nuclear accumulation of Nrf2 in aortic VSMC from normotensive but not spontaneously hypertensive rats, as an antioxidant defence response to enhanced ROS generation and oxidative stress 6.…”

Section: Discussionmentioning

confidence: 80%

“…AngII plays a central role in the development of hypertension and atherosclerosis through an increase in reactive oxygen species (ROS) generation and down‐regulation of endogenous antioxidant defence systems such as Nrf2 4, 5, 6. AngII has been also shown to induce senescence and apoptosis in vascular smooth muscle cells (VSMC) via activation of the cell cycle regulation proteins p53 and p21 7.…”

Section: Introductionmentioning

confidence: 99%

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The anti‐ageing hormone klotho induces Nrf2‐mediated antioxidant defences in human aortic smooth muscle cells

Maltese

Psefteli

Rizzo

et al. 2016

J Cellular Molecular Medi

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Vascular ageing in conditions such as atherosclerosis, diabetes and chronic kidney disease, is associated with the activation of the renin angiotensin system (RAS) and diminished expression of antioxidant defences mediated by the transcription factor nuclear factor erythroid 2‐related factor 2 (Nrf2). The anti‐ageing hormone klotho promotes longevity and protects against cardiovascular and renal diseases. Klotho has been shown to activate Nrf2 and attenuate oxidative damage in neuronal cells, however, the mechanisms by which it protects against vascular smooth muscle cell VSMC dysfunction elicited by Angiotensin II (AngII) remain to be elucidated. AngII contributes to vascular ageing and atherogenesis by enhancing VSMC oxidative stress, senescence and apoptosis. This study demonstrates that soluble klotho (1 nM, 24 hrs) significantly induces expression of Nrf2 and the antioxidant enzymes haeme oxygenase (HO‐1) and peroxiredoxin‐1 (Prx‐1) and enhances glutathione levels in human aortic smooth muscle cells (HASMC). Silencing of Nrf2 attenuated the induction of HO‐1 and Prx‐1 expression by soluble klotho. Furthermore, soluble klotho protected against AngII‐mediated HASMC apoptosis and senescence via activation of Nrf2. Thus, our findings highlight a novel Nrf2‐mediated mechanism underlying the protective actions of soluble klotho in HAMSC. Targeting klotho may thus represent a therapeutic strategy against VSMC dysfunction and cardiovascular ageing.

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Section: Discussionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

The anti‐ageing hormone klotho induces Nrf2‐mediated antioxidant defences in human aortic smooth muscle cells

Maltese

Psefteli

Rizzo

et al. 2016

J Cellular Molecular Medi

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“…38 In this setting, Nrf2 activator, Nox1, and Rho kinase inhibitors normalized vascular function, 38 indicating that Nrf2 is clearly vasoprotective. Similarly, Nrf2 downregulation has been observed in arteries from stroke-prone spontaneously hypertensive rats, 39 which contributes to redoxsensitive vascular dysfunction in hypertension. Angiotensin II increased nuclear accumulation of Nrf2 in VSMCs from Wistar Kyoto rats, with blunted effects in stroke-prone spontaneously hypertensive rats 39 .…”

mentioning

confidence: 94%

Oxidative Stress, Inflammation, and Vascular Aging in Hypertension

2017

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Figure.Central role of oxidative stress in accelerated vascular aging in hypertension. AT1R indicates angiotensin II receptor type 1; BH 2 , dihydrobiopterin; BH 4 , tetrahydrobiopterin; BMP, bone morphogenic protein; CypD, cyclophilin D; eNOS, endothelial NO synthase; ET1R, endothelin 1 receptor; H 2 O 2 , hydrogen peroxide; MMP, matrix metalloproteinase; Nox, NADPH oxidase; O 2 −. , superoxide anion; RANTES, regulated on activation, normal T cell expressed and secreted chemokine; and SmgGDS, GTP-binding protein dissociation stimulator. by guest on

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“…Some studies have reported that Nrf2 activators attenuate blood pressure elevation in hypertension models 34,35 via regulation of myogenic tone due to increased expression of Nrf2-regulated antioxidant genes in vascular smooth muscle. 24 As vascular Nrf2-antioxidant system may exert vasoprotective effects in hypertension-associated vascular changes induced by increased vascular oxidative stress, the effects of the BM may be related to the decrease in SBP by BM in the Ald-and salt-induced model. Although decrease in blood pressure is reported not to lead to attenuation of renal injury and reduction of oxidative stress in the Ald-and salt-induced renal injury model, 18,36 such vasoprotective actions of BM may be useful for the improvement of vascular function in hypertension.…”

Section: Discussionmentioning

confidence: 99%

“…23 In hypertension models, Nrf2 activators were reported to be related to improvement of vascular function via antioxidant property. 24 Its effects might therefore be expected to extend to tubulointerstitial injury due to salt-sensitive hypertension.…”

Section: Introductionmentioning

confidence: 99%

Role of bardoxolone methyl, a nuclear factor erythroid 2-related factor 2 activator, in aldosterone- and salt-induced renal injury

Hisamichi¹,

Kamijo‐Ikemori

Sugaya³

et al. 2017

Hypertens Res

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The aim of this study was to investigate the renoprotective effect of bardoxolone methyl (BM), a nuclear factor erythroid 2-related factor 2 (Nrf2) activator with an antioxidant effect, in a salt-sensitive hypertension model induced by aldosterone (Ald) and salt. Tubulointerstitial damage with urinary liver-type fatty acid-binding protein (L-FABP) was evaluated using human L-FABP chromosomal transgenic (L-FABP +/ − ) male mice. The mice in the Ald group (n = 7) received systemic Ald infusions via an osmotic minipump and were given 1% NaCl water for 35 days. Those in the Ald-BM group (n = 8) were administered BM intraperitoneally in addition to an injection of Ald and salt. The dose of BM was gradually increased every 7 days up to 10 mg kg − 1 per day, which was maintained for 14 days. The administration of BM significantly increased renal expression of the Nrf2 target antioxidant gene. Tubulointerstitial damage was significantly ameliorated in the Ald-BM group compared to the Ald group. The increase in reactive oxygen species (ROS) and upregulation of angiotensinogen expression in the kidneys of the Ald group was significantly prevented in the Ald-BM group. The upregulation of human L-FABP expression induced in the kidneys and increase in urinary L-FABP in the Ald group were significantly suppressed by BM administration. In conclusion, BM ameliorated tubulointerstitial damage in the Ald-and salt-induced hypertension model through suppression of both ROS production and intrarenal renin-angiotensin system activation. Urinary L-FABP may be a useful marker reflecting the therapeutic efficacy of BM.

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Downregulation of Nuclear Factor Erythroid 2–Related Factor and Associated Antioxidant Genes Contributes to Redox-Sensitive Vascular Dysfunction in Hypertension

Cited by 114 publications

References 39 publications

The anti‐ageing hormone klotho induces Nrf2‐mediated antioxidant defences in human aortic smooth muscle cells

The anti‐ageing hormone klotho induces Nrf2‐mediated antioxidant defences in human aortic smooth muscle cells

Oxidative Stress, Inflammation, and Vascular Aging in Hypertension

Role of bardoxolone methyl, a nuclear factor erythroid 2-related factor 2 activator, in aldosterone- and salt-induced renal injury

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