scholarly journals Angiotensin II Induces Oxidative Stress and Endothelial Dysfunction in Mouse Ophthalmic Arteries via Involvement of AT1 Receptors and NOX2

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1238
Author(s):  
Michael Birk ◽  
Ewa Baum ◽  
Jenia Kouchek Zadeh ◽  
Caroline Manicam ◽  
Norbert Pfeiffer ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Point Of View ◽  
Ang Ii ◽  
Ocular Diseases ◽  
Underlying Mechanisms ◽  
Ophthalmic Arteries

Angiotensin II (Ang II) has been implicated in the pathophysiology of various age-dependent ocular diseases. The purpose of this study was to test the hypothesis that Ang II induces endothelial dysfunction in mouse ophthalmic arteries and to identify the underlying mechanisms. Ophthalmic arteries were exposed to Ang II in vivo and in vitro to determine vascular function by video microscopy. Moreover, the formation of reactive oxygen species (ROS) was quantified and the expression of prooxidant redox genes and proteins was determined. The endothelium-dependent artery responses were blunted after both in vivo and in vitro exposure to Ang II. The Ang II type 1 receptor (AT1R) blocker, candesartan, and the ROS scavenger, Tiron, prevented Ang II-induced endothelial dysfunction. ROS levels and NOX2 expression were increased following Ang II incubation. Remarkably, Ang II failed to induce endothelial dysfunction in ophthalmic arteries from NOX2-deficient mice. Following Ang II incubation, endothelium-dependent vasodilation was mainly mediated by cytochrome P450 oxygenase (CYP450) metabolites, while the contribution of nitric oxide synthase (NOS) and 12/15-lipoxygenase (12/15-LOX) pathways became negligible. These findings provide evidence that Ang II induces endothelial dysfunction in mouse ophthalmic arteries via AT1R activation and NOX2-dependent ROS formation. From a clinical point of view, the blockade of AT1R signaling and/or NOX2 may be helpful to retain or restore endothelial function in ocular blood vessels in certain ocular diseases.

Angiotensin II modulates frizzled-2 receptor expression in rat vascular smooth muscle cells

2005 ◽  
Vol 108 (6) ◽  
pp. 523-530 ◽  
Author(s):  
Giovanna CASTOLDI ◽  
Serena REDAELLI ◽  
Willy M. M. van de GREEF ◽  
Cira R. T. di GIOIA ◽  
Giuseppe BUSCA ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
Ang Ii ◽  
Aortic Smooth Muscle

Ang II (angiotensin II) has multiple effects on vascular smooth muscle cells through the modulation of different classes of genes. Using the mRNA differential-display method to investigate gene expression in rat aortic smooth muscle cells in culture in response to 3 h of Ang II stimulation, we observed that Ang II down-regulated the expression of a member of the family of transmembrane receptors for Wnt proteins that was identified as Fzd2 [Fzd (frizzled)-2 receptor]. Fzds are a class of highly conserved genes playing a fundamental role in the developmental processes. In vitro, time course experiments demonstrated that Ang II induced a significant increase (P<0.05) in Fzd2 expression after 30 min, whereas it caused a significant decrease (P<0.05) in Fzd2 expression at 3 h. A similar rapid up-regulation after Ang II stimulation for 30 min was evident for TGFβ1 (transforming growth factor β1; P<0.05). To investigate whether Ang II also modulated Fzd2 expression in vivo, exogenous Ang II was administered to Sprague–Dawley rats (200 ng·kg−1 of body weight·min−1; subcutaneously) for 1 and 4 weeks. Control rats received normal saline. After treatment, systolic blood pressure was significantly higher (P<0.01), whereas plasma renin activity was suppressed (P<0.01) in Ang II- compared with the saline-treated rats. Ang II administration for 1 week did not modify Fzd2 expression in aorta of Ang II-treated rats, whereas Ang II administration for 4 weeks increased Fzd2 mRNA expression (P<0.05) in the tunica media of the aorta, resulting in a positive immunostaining for fibronectin at this time point. In conclusion, our data demonstrate that Ang II modulates Fzd2 expression in aortic smooth muscle cells both in vitro and in vivo.

Abstract MP03: ROCK2 Specific Inhibition Attenuates Angiotensin II-induced Hypertension In Mice

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Daniel J Fehrenbach ◽  
Meena S Madhur
Keyword(s):  
Blood Pressure ◽  
T Cell ◽  
Angiotensin Ii ◽  
Repeated Measures ◽  
Flow Cytometric Analysis ◽  
Coiled Coil ◽  
Ang Ii ◽  
Induced Hypertension

Hypertension, or an elevated blood pressure, is the primary modifiable risk factor for cardiovascular disease, the number one cause of mortality worldwide. We previously demonstrated that Th17 activation and interleukin 17A (IL-17A)/IL-21 production is integral for the full development of a hypertensive phenotype as well as the renal and vascular damage associated with hypertension. Rho-associated coiled-coil containing protein Kinase 2 (ROCK2) serves as a molecular switch upregulating Th17 and inhibiting regulatory T cell (Treg) differentiation. We hypothesize that hypertension is characterized by excessive T cell ROCK2 activation leading to increased Th17/Treg ratios and ultimately end-organ damage. We first showed in vitro that KD025, an experimental orally bioavailable ROCK2 inhibitor inhibits Th17 cell proliferation and IL-17A/IL-21 production. To determine if hypertensive stimuli such as endothelial stretch increases T cell ROCK2 expression, we cultured human aortic endothelial cells exposed to 5% (normotensive) or 10% (hypertensive) stretch with circulating human T cells and HLA-DR+ antigen presenting cells. Hypertensive stretch increased T cell ROCK2 expression 2-fold. We then tested the effect of ROCK2 inhibition with KD025 (50mg/kg i.p. daily) in vivo on angiotensin II (Ang II)-induced hypertension. Treatment with KD025 significantly attenuated the hypertensive response within 1 week of Ang II treatment (systolic blood pressure: 139± 8 vs 108±7mmHg) and this persisted for the duration of the 4 week study reaching blood pressures 20 mmHg lower (135±13mmHg) than vehicle treated mice (158±4mmHg p<0.05 effect of treatment 2-way Repeated Measures ANOVA). Flow cytometric analysis of tissue infiltrating leukocytes revealed that KD025 treatment increased Treg/Th17 ratios in the kidney (0.61±0.03 vs 0.79±0.08, p<0.05 student’s t-test). Thus, T cell ROCK2 may be a novel therapeutic target for the treatment of hypertension.

Abstract 229: TNF Receptor 1 Signaling Is Critically Involved in Mediating Angiotensin II-Induced Cardiac Fibrosis and Dysfunction

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Sandra B Haudek ◽  
Jeff Crawford ◽  
Erin Reineke ◽  
Alberto A Allegre ◽  
George E Taffet ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Fibrosis ◽  
Smooth Muscle Actin ◽  
Protein A ◽  
Ang Ii ◽  
Wild Type ◽  
Monocyte Chemoattractant Protein 1 ◽  
Reactive Fibrosis

Angiotensin-II (Ang-II) plays a key role in the development of cardiomyopathies, as it is associated with many conditions involving heart failure and pathologic hypertrophy. Using a murine model of Ang-II infusion, we found that Ang-II induced the synthesis of monocyte chemoattractant protein 1 (MCP-1) that mediated the uptake of CD34 + /CD45 + monocytic cells into the heart. These precursor cells differentiated into collagen-producing fibroblasts and were responsible for the Ang-II-induced development of reactive fibrosis. Preliminary in vitro data using our monocyte-to-fibroblast differentiation model, suggested that Ang-II required the presence of TNF to induce fibroblast maturation from monocytes. In vivo, they indicated that in mice deficient of both TNF receptors (TNFR1 and TNFR2), Ang-II-induced fibrosis was absent. We now assessed the hypothesis that specific TNFR1 signaling is necessary for Ang-II-mediated cardiac fibrosis. Mice deficient in either TNFR1 (TNFR1-KO) or TNFR2 (TNFR2-KO) were subjected to continuous infusion of Ang-II for 1 to 6 weeks (n=6-8/group). Compared to wild-type, we found that in TNFR1-KO, but not in TNFR2-KO mouse hearts, collagen deposition was attenuated, as was cardiac α-smooth muscle actin protein (a marker for activated fibroblasts). When we isolated viable cardiac fibroblasts and characterized them by flow cytometry, we found that Ang-II infusion in TNFR1-KO, but not in TNFR2-KO, resulted in a marked decrease of CD34 + /CD45 + cells. Quantitative RT-PCR demonstrated a striking reduction of type 1 and 3 collagen, as well of MCP-1 mRNA expression in TNFR1-KO mouse hearts. Further measurements of cardiovascular parameters indicated that TNFR1-KO animals developed lesser Ang-II-mediated LV remodeling, smaller changes in E-linear deceleration times/rates over time, and displayed a lower Tei index (a heart rate independent marker of cardiac function), indicating less stiffness in TNFR1-KO hearts compared to wild-type and TNFR2-KO hearts. The data suggest that Ang-II-dependent cardiac fibrosis requires TNF and its signaling through TNFR1 which enhances the induction of MCP-1 and uptake of monocytic fibroblast precursors that are associated with reactive fibrosis and cardiac remodeling and function.

Neuronal excitation by angiotensin II in the rostral ventrolateral medulla of the rat in vitro

1995 ◽  
Vol 268 (1) ◽  
pp. R272-R277 ◽  
Author(s):  
Y. W. Li ◽  
P. G. Guyenet
Keyword(s):  
Angiotensin Ii ◽  
Excitatory Amino Acid ◽  
Rostral Ventrolateral Medulla ◽  
Ventrolateral Medulla ◽  
Ang Ii ◽  
Excitatory Amino Acid Receptor ◽  
Neuronal Excitation ◽  
Uk 14,304

We examined the effects of angiotensin II (ANG II) on spontaneous unit activity in slices of the rat rostral ventrolateral medulla (RVLM), ANG II (1-3 microM) excited 61% of a population of slowly and irregularly firing RVLM neurons (predrug, 1.2 +/- 0.1 spikes/s; postdrug, 4.6 +/- 0.3 spikes/s; n = 52). ANG II had no effect on pacemaker-like rapidly firing neurons (predrug, 8.6 +/- 0.4 spikes/s; n = 33). The effect of ANG II on slowly firing cells was repeatable and was reduced 75% by 3 microM losartan (baseline, 1.7 +/- 0.4 spikes/s; ANG II, 5.3 +/- 0.7 spikes/s; ANG II+losartan, 2.4 +/- 0.6 spikes/s; n = 12). The ongoing activity of slowly firing neurons was unaffected by 0.5-1 mM kynurenic acid (an ionotropic excitatory amino acid receptor antagonist). Most ANG II-responsive neurons (10 of 11) were inhibited by the alpha 2-adrenergic receptor agonist UK-14,304, but pacemaker-like neurons were not. In conclusion, the RVLM contains neurons excited by AT1 receptor agonists. These neurons are distinct from the previously described pacemaker nonadrenergic presympathetic cells. They may be responsible for the pressor effects produced by injecting ANG II into the RVLM in vivo.

Glomerular effects of angiotensin II require intrarenal factors

1990 ◽  
Vol 258 (3) ◽  
pp. F717-F721 ◽  
Author(s):  
T. B. Wiegmann ◽  
M. L. MacDougall ◽  
V. J. Savin
Keyword(s):  
Angiotensin Ii ◽  
Rate Of Change ◽  
Ang Ii ◽  
Membrane Area ◽  
Isolated Glomeruli ◽  
Systemic Factors ◽  
Glomerular Ultrafiltration

Glomerular ultrafiltration coefficient (Kf) of glomeruli isolated from kidneys of normovolemic rats decreases following infusion of angiotensin II (ANG II). Kf from isolated glomeruli after ANG II infusion in vivo and from isolated perfused kidneys following infusion of ANG II in vitro was measured to determine whether the decrease required the presence of systemic factors. Filtration was induced in vitro and the maximum rate of change in glomerular volume was used to calculate Kf. Glomerular capillary hydraulic conductivity (Lp) was calculated from Lp = Kf/A where the basement membrane area A was calculated as 3 X pi X D2. ANG II infusion in vivo in rats diminished Lp from 3.19 +/- 0.19 to 1.96 +/- 0.13 and to 1.82 +/- 0.11 microliters.min-1.mmHg-1.cm-2, respectively. ANG II infusion into isolated kidneys caused a similar decrease in Lp (3.55 +/- 0.11 to 2.37 +/- 0.07). ANG II infusion either in vivo or during isolated kidney perfusion decreases Kf and Lp. ANG II effects do not require the presence of extrarenal factors but depend on perfusion in situ since incubation of isolated glomeruli with ANG II did not alter Kf.

scholarly journals Autophagy inhibition by chloroquine prevents increase in blood pressure and preserves endothelial functions

2020 ◽  
Vol 19 (4) ◽  
pp. 789-796
Author(s):  
Moon Jain ◽  
Hina Iqbal ◽  
Pankaj Yadav ◽  
Himalaya Singh ◽  
Debabrata Chanda ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cell Migration ◽  
Endothelial Cell ◽  
Angiotensin Ii ◽  
Ang Ii ◽  
Hypertensive Rats ◽  
Autophagy Flux ◽  
Endothelial Functions

Purpose: To determine the effects of lysosomal inhibition of autophagy by chloroquine (CHQ) onhypertension-associated changes in the endothelial functions. Method: Angiotensin II (Ang II)-treated human endothelial cell line EA.hy926 and renovascularhypertensive rats were subjected to CHQ treatment (in vitro: 0.5, 1, and 2.5 μM; in vivo: 50 mg/kg/dayfor three weeks). Changes in the protein expressions of LC3b II (autophagosome formation marker) andp62 (autophagy flux marker) were assessed using immunoblotting. Cell migration assay, tubuleformation assay (in vitro), and organ bath studies (in vivo) were performed to evaluate the endothelialfunctions. Hemodynamic parameters were measured as well. Results: A higher expression of LC3b II and a reduced expression of p62 observed in the Ang II-treatedendothelial cells, as well as in the aorta of the hypertensive rats, indicated enhanced autophagy.Treatment with CHQ resulted in reduced autophagy flux (in vitro as well as in vivo) and suppressed AngII-induced endothelial cell migration and angiogenesis (in vitro). The treatment with CHQ was alsoobserved to prevent increase in blood pressure in hypertensive rats and preserved acetylcholineinducedrelaxation in phenylephrine-contracted aorta from the hypertensive rats. In addition, chloroquineattenuated Ang II-induced contractions in the aorta of normotensive as well as hypertensive rats. Conclusion: These observations indicated that CHQ lowers the blood pressure and preserves thevascular endothelial function during hypertension. Keywords: Angiotensin II, Autophagy, Chloroquine, Endothelial function, Hypertension, Vasculardysfunction

scholarly journals Proximal tubule NHE3 activity is inhibited by beta-arrestin-biased angiotensin II type 1 receptor signaling

2015 ◽  
Vol 309 (8) ◽  
pp. C541-C550 ◽  
Author(s):  
Carla P. Carneiro de Morais ◽  
Juliano Z. Polidoro ◽  
Donna L. Ralph ◽  
Thaissa D. Pessoa ◽  
Maria Oliveira-Souza ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Proximal Tubule ◽  
G Protein ◽  
Extracellular Fluid ◽  
The Body ◽  
Type I ◽  
Ang Ii ◽  
Receptor Signaling

Physiological concentrations of angiotensin II (ANG II) upregulate the activity of Na+/H+ exchanger isoform 3 (NHE3) in the renal proximal tubule through activation of the ANG II type I (AT1) receptor/G protein-coupled signaling. This effect is key for maintenance of extracellular fluid volume homeostasis and blood pressure. Recent findings have shown that selective activation of the beta-arrestin-biased AT1 receptor signaling pathway induces diuresis and natriuresis independent of G protein-mediated signaling. This study tested the hypothesis that activation of this AT1 receptor/beta-arrestin signaling inhibits NHE3 activity in proximal tubule. To this end, we determined the effects of the compound TRV120023, which binds to the AT1R, blocks G-protein coupling, and stimulates beta-arrestin signaling on NHE3 function in vivo and in vitro. NHE3 activity was measured in both native proximal tubules, by stationary microperfusion, and in opossum proximal tubule (OKP) cells, by Na+-dependent intracellular pH recovery. We found that 10−7 M TRV120023 remarkably inhibited proximal tubule NHE3 activity both in vivo and in vitro. Additionally, stimulation of NHE3 by ANG II was completely suppressed by TRV120023 both in vivo as well as in vitro. Inhibition of NHE3 activity by TRV120023 was associated with a decrease in NHE3 surface expression in OKP cells and with a redistribution from the body to the base of the microvilli in the rat proximal tubule. These findings indicate that biased signaling of the beta-arrestin pathway through the AT1 receptor inhibits NHE3 activity in the proximal tubule at least in part due to changes in NHE3 subcellular localization.

scholarly journals COX-2 mediates angiotensin II-induced (pro)renin receptor expression in the rat renal medulla

2014 ◽  
Vol 307 (1) ◽  
pp. F25-F32 ◽  
Author(s):  
Fei Wang ◽  
Xiaohan Lu ◽  
Kexin Peng ◽  
Li Zhou ◽  
Chunling Li ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Protein Expression ◽  
Renal Medulla ◽  
Receptor Expression ◽  
Ang Ii ◽  
Cox 2 ◽  
Renin Content

(Pro)renin receptor (PRR) is predominantly expressed in the distal nephron where it is activated by angiotensin II (ANG II), resulting in increased renin activity in the renal medulla thereby amplifying the de novo generation and action of local ANG II. The goal of the present study was to test the role of cycloxygenase-2 (COX-2) in meditating ANG II-induced PRR expression in the renal medulla in vitro and in vivo. Exposure of primary rat inner medullary collecting duct cells to ANG II induced sequential increases in COX-2 and PRR protein expression. When the cells were pretreated with a COX-2 inhibitor NS-398, ANG II-induced upregulation of PRR protein expression was almost completely abolished, in parallel with the changes in medium active renin content. The inhibitory effect of NS-398 on the PRR expression was reversed by adding exogenous PGE2. A 14-day ANG II infusion elevated renal medullary PRR expression and active and total renin content in parallel with increased urinary renin, all of which were remarkably suppressed by the COX-2 inhibitor celecoxib. In contrast, plasma and renal cortical active and total renin content were suppressed by ANG II treatment, an effect that was unaffected by COX-2 inhibition. Systolic blood pressure was elevated with ANG II infusion, which was attenuated by the COX-2 inhibition. Overall, the results obtained from in vitro and in vivo studies established a crucial role of COX-2 in mediating upregulation of renal medullary PRR expression and renin content during ANG II hypertension.

scholarly journals Interference with PPARγ in endothelium accelerates angiotensin II-induced endothelial dysfunction

2016 ◽  
Vol 48 (2) ◽  
pp. 124-134 ◽  
Author(s):  
Chunyan Hu ◽  
Ko-Ting Lu ◽  
Masashi Mukohda ◽  
Deborah R. Davis ◽  
Frank M. Faraci ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Carotid Arteries ◽  
Pressor Response ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Ang Ii ◽  
Specific Expression ◽  
Stress Dependent

The ligand activated nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) in the endothelium regulates vascular function and blood pressure (BP). We previously reported that transgenic mice (E-V290M) with selectively targeted endothelial-specific expression of dominant negative PPARγ exhibited endothelial dysfunction when treated with a high-fat diet, and exhibited an augmented pressor response to angiotensin II (ANG II). We hypothesize that interference with endothelial PPARγ would exacerbate ANG II-induced endothelial dysfunction. Endothelial function was examined in E-V290M mice infused with a subpressor dose of ANG II (120 ng·kg−1·min−1) or saline for 2 wk. ANG II infusion significantly impaired the responses to the endothelium-dependent agonist acetylcholine both in basilar and carotid arteries from E-V290M but not NT mice. This impairment was not due to increased BP, which was not significantly different in ANG II-infused E-V290M compared with NT mice. Superoxide levels, and expression of the pro-oxidant Nox2 gene was elevated, whereas expression of the anti-oxidant genes Catalase and SOD3 decreased in carotid arteries from ANG II-infused E-V290M mice. Increased p65 and decreased Iκ-Bα suggesting increased NF-κB activity was also observed in aorta from ANG II-infused E-V290M mice. The responses to acetylcholine were significantly improved both in basilar and carotid arteries after treatment with Tempol (1 mmol/l), a scavenger of superoxide. These findings provide evidence that interference with endothelial PPARγ accelerates ANG II-mediated endothelial dysfunction both in cerebral and conduit arteries through an oxidative stress-dependent mechanism, suggesting a role for endothelial PPARγ in protecting against ANG II-induced endothelial dysfunction.

Sign in / Sign up

Export Citation Format

Share Document