The homeostatic role of hydrogen peroxide, superoxide anion and nitric oxide in the vasculature

Costa, Tiago J.; Barros, Pedro Paulo; Arce, Cristina; Santos, Jeimison Duarte; Silva-Neto, Júlio da; Egea, Gustavo; Dantas, Ana Paula; Tostes, Rita C.; Jiménez‐Altayó, Francesc

doi:10.1016/j.freeradbiomed.2020.11.021

Cited by 66 publications

(60 citation statements)

References 313 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…ROS have physiological roles [ 10 , 34 , 35 ]. However, when the generation of these volatile species is exacerbated, and cells are no longer able to handle them, the consequent malfunction of cells leads to and aggravates pathological conditions.…”

Section: Discussionmentioning

confidence: 99%

Aldosterone Negatively Regulates Nrf2 Activity: An Additional Mechanism Contributing to Oxidative Stress and Vascular Dysfunction by Aldosterone

Rodrigues

Costa

Silva

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

High levels of aldosterone (Aldo) trigger oxidative stress and vascular dysfunction independent of effects on blood pressure. We sought to determine whether Aldo disrupts Nrf2 signaling, the main transcriptional factor involved in antioxidant responses that aggravate cell injury. Thoracic aorta from male C57Bl/6J mice and cultured human endothelial cells (EA.hy926) were stimulated with Aldo (100 nM) in the presence of tiron [reactive oxygen species (ROS) scavenger, eplerenone [mineralocorticoid receptor (MR) antagonist], and L-sulforaphane (SFN; Nrf2 activator). Thoracic aortas were also isolated from mice infused with Aldo (600 μg/kg per day) for 14 days. Aldo decreased endothelium-dependent vasorelaxation and increased ROS generation, effects prevented by tiron and MR blockade. Pharmacological activation of Nrf2 with SFN abrogated Aldo-induced vascular dysfunction and ROS generation. In EA.hy926 cells, Aldo increased ROS generation, which was prevented by eplerenone, tiron, and SFN. At short times, Aldo-induced ROS generation was linked to increased Nrf2 activation. However, after three hours, Aldo decreased the nuclear accumulation of Nrf2. Increased Keap1 protein expression, but not activation of p38 MAPK, was linked to Aldo-induced reduced Nrf2 activity. Arteries from Aldo-infused mice also exhibited decreased nuclear Nrf2 and increased Keap1 expression. Our findings suggest that Aldo reduces vascular Nrf2 transcriptional activity by Keap1-dependent mechanisms, contributing to mineralocorticoid-induced vascular dysfunction.

show abstract

Section: Discussionmentioning

confidence: 99%

Aldosterone Negatively Regulates Nrf2 Activity: An Additional Mechanism Contributing to Oxidative Stress and Vascular Dysfunction by Aldosterone

Rodrigues

Costa

Silva

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…They are continuously produced and transformed in response to several endogenous and exogenous stimuli under physiopathological conditions. ROS are involved in several biological processes such as cellular growth, immune response, embryogenesis, spermatozoa capacitation, and transcription factor activation [ 44 , 65 ]. Furthermore, ROS regulate vascular functions (e.g., vasodilatation, vasoconstriction, angiogenesis, migration, and apoptosis) [ 41 , 44 , 45 , 46 ].…”

Section: Ros Production and Elimination In Endothelial Cellsmentioning

confidence: 99%

“…ROS are involved in several biological processes such as cellular growth, immune response, embryogenesis, spermatozoa capacitation, and transcription factor activation [ 44 , 65 ]. Furthermore, ROS regulate vascular functions (e.g., vasodilatation, vasoconstriction, angiogenesis, migration, and apoptosis) [ 41 , 44 , 45 , 46 ]. Thus, there is a finely regulated balance between ROS production and ROS degradation [ 46 ].…”

Section: Ros Production and Elimination In Endothelial Cellsmentioning

confidence: 99%

“…Reactive oxygen species (ROS), which are produced in vascular endothelial cells during their metabolic activity or upon extracellular stimulation ( Figure 1 ), might also serve as a double-edged sword [ 44 , 45 , 46 ]. Endothelial ROS signaling is exploited by mechanical and chemical cues to regulate a number of vascular functions that often overlap with those controlled by Ca 2+ , e.g., EDH [ 47 ], vascular permeability [ 48 ], leukocyte infiltration [ 49 ], platelet aggregation [ 50 ], gene expression [ 51 ], angiogenesis [ 45 , 52 ], and vasculogenesis [ 53 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Reactive Oxygen Species and Endothelial Ca2+ Signaling: Brothers in Arms or Partners in Crime?

Negri¹,

Faris²,

Moccia³

2021

IJMS

View full text Add to dashboard Cite

An increase in intracellular Ca2+ concentration ([Ca2+]i) controls virtually all endothelial cell functions and is, therefore, crucial to maintain cardiovascular homeostasis. An aberrant elevation in endothelial can indeed lead to severe cardiovascular disorders. Likewise, moderate amounts of reactive oxygen species (ROS) induce intracellular Ca2+ signals to regulate vascular functions, while excessive ROS production may exploit dysregulated Ca2+ dynamics to induce endothelial injury. Herein, we survey how ROS induce endothelial Ca2+ signals to regulate vascular functions and, vice versa, how aberrant ROS generation may exploit the Ca2+ handling machinery to promote endothelial dysfunction. ROS elicit endothelial Ca2+ signals by regulating inositol-1,4,5-trisphosphate receptors, sarco-endoplasmic reticulum Ca2+-ATPase 2B, two-pore channels, store-operated Ca2+ entry (SOCE), and multiple isoforms of transient receptor potential (TRP) channels. ROS-induced endothelial Ca2+ signals regulate endothelial permeability, angiogenesis, and generation of vasorelaxing mediators and can be exploited to induce therapeutic angiogenesis, rescue neurovascular coupling, and induce cancer regression. However, an increase in endothelial [Ca2+]i induced by aberrant ROS formation may result in endothelial dysfunction, inflammatory diseases, metabolic disorders, and pulmonary artery hypertension. This information could pave the way to design alternative treatments to interfere with the life-threatening interconnection between endothelial ROS and Ca2+ signaling under multiple pathological conditions.

show abstract

“…Indeed, ROS overproduction represents an upstream key event of different pathways involved in diabetic vascular damage [ 20 , 21 ]. Under physiological conditions, cellular antioxidant mechanisms keep levels of ROS in check [ 22 ]. However, aberrant regulation of these mechanisms leads to dramatic increases in ROS levels, thereby precipitating various pathological conditions [ 20 , 21 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

Resveratrol-Elicited PKC Inhibition Counteracts NOX-Mediated Endothelial to Mesenchymal Transition in Human Retinal Endothelial Cells Exposed to High Glucose

et al. 2021

View full text Add to dashboard Cite

Diabetes-associated long-term hyperglycaemia leads to oxidative stress-mediated fibrosis in different tissues and organs. Endothelial-to-mesenchymal-transition (EndMT) appears to play a role in diabetes-associated fibrotic conditions. Here, we investigate whether EndMT is implicated in the diabetic retinopathy fibrotic process and evaluate the possibility that resveratrol could counteract EndMT by inhibiting high glucose (HG)-induced increases in ROS. Primary Human Retinal Endothelial Cells (HRECs) were either pre-treated for 24 h with 1 µM resveratrol or left untreated, then glucose (30 mM) was applied at 3-day intervals for 10 days. qRT-PCR and ELISA were used to detect mRNA or protein expression of endothelial markers (CD31, CDH5, vWF) or mesenchymal markers (VIM, αSMA and collagen I), respectively. Intracellular ROS levels were measured with carboxy-DCFDA, while NOX-associated ROS levels were evaluated using the NADPH-specific redox biosensor p47-roGFP. Treatment of HRECs with HG increased intracellular ROS levels and promoted phenotype shifting towards EndMT, evidenced by decreased expression of endothelial markers concomitant with increased expression of mesenchymal ones. HG-induced EndMT appears to be mediated by NADPH-associated ROS generation as pre-treatment of HRECs with resveratrol or the NADPH inhibitor, diphenyleneiodonium chloride (DPI), attenuated ROS production and EndMT transition, suggesting that the effect of resveratrol on HG-induced ROS occurs via down-regulation of NADPH oxidase. It is worth noting that resveratrol or Chelerythrine, a Protein kinase C (PKC) inhibitor, reduce ROS and EndMT in HG-exposed cells, suggesting that NADPH activation occurs via a PKC-dependent mechanism. Taken together, our results provide the basis for a resveratrol-based potential protective therapy to prevent diabetic-associated complications.

show abstract

The homeostatic role of hydrogen peroxide, superoxide anion and nitric oxide in the vasculature

Cited by 66 publications

References 313 publications

Aldosterone Negatively Regulates Nrf2 Activity: An Additional Mechanism Contributing to Oxidative Stress and Vascular Dysfunction by Aldosterone

Aldosterone Negatively Regulates Nrf2 Activity: An Additional Mechanism Contributing to Oxidative Stress and Vascular Dysfunction by Aldosterone

Reactive Oxygen Species and Endothelial Ca2+ Signaling: Brothers in Arms or Partners in Crime?

Resveratrol-Elicited PKC Inhibition Counteracts NOX-Mediated Endothelial to Mesenchymal Transition in Human Retinal Endothelial Cells Exposed to High Glucose

Contact Info

Product

Resources

About