Dietary restriction but not angiotensin II type 1 receptor blockade improves DNA damage-related vasodilator dysfunction in rapidly aging Ercc1Δ/− mice

2017 ◽  
Vol 131 (15) ◽  
pp. 1941-1953 ◽  
Author(s):  
Haiyan Wu ◽  
Bibi S. van Thiel ◽  
Paula K. Bautista-Niño ◽  
Erwin Reiling ◽  
Matej Durik ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Dna Damage ◽  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Dietary Restriction ◽  
Organ Bath ◽  
Receptor Blockade ◽  
Ang Ii ◽  
No Signaling

DNA damage is an important contributor to endothelial dysfunction and age-related vascular disease. Recently, we demonstrated in a DNA repair-deficient, prematurely aging mouse model (Ercc1Δ/− mice) that dietary restriction (DR) strongly increases life- and health span, including ameliorating endothelial dysfunction, by preserving genomic integrity. In this mouse mutant displaying prominent accelerated, age-dependent endothelial dysfunction we investigated the signaling pathways involved in improved endothelium-mediated vasodilation by DR, and explore the potential role of the renin-angiotensin system (RAS). Ercc1Δ/− mice showed increased blood pressure and decreased aortic relaxations to acetylcholine (ACh) in organ bath experiments. Nitric oxide (NO) signaling and phospho-Ser1177-eNOS were compromised in Ercc1Δ/−. DR improved relaxations by increasing prostaglandin-mediated responses. Increase of cyclo-oxygenase 2 and decrease of phosphodiesterase 4B were identified as potential mechanisms. DR also prevented loss of NO signaling in vascular smooth muscle cells and normalized angiotensin II (Ang II) vasoconstrictions, which were increased in Ercc1Δ/− mice. Ercc1Δ/− mutants showed a loss of Ang II type 2 receptor-mediated counter-regulation of Ang II type 1 receptor-induced vasoconstrictions. Chronic losartan treatment effectively decreased blood pressure, but did not improve endothelium-dependent relaxations. This result might relate to the aging-associated loss of treatment efficacy of RAS blockade with respect to endothelial function improvement. In summary, DR effectively prevents endothelium-dependent vasodilator dysfunction by augmenting prostaglandin-mediated responses, whereas chronic Ang II type 1 receptor blockade is ineffective.

Angiotensin II mediates uterine vasoconstriction through α-stimulation

2004 ◽  
Vol 287 (1) ◽  
pp. H126-H134 ◽  
Author(s):  
Blair E. Cox ◽  
Timothy A. Roy ◽  
Charles R. Rosenfeld
Keyword(s):  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Receptor Blockade ◽  
Ang Ii ◽  
Pressor Responses ◽  
Adrenergic Activation

Intravenous angiotensin II (ANG II) increases uterine vascular resistance (UVR), whereas uterine intra-arterial infusions do not. Type 2 ANG II (AT2) receptors predominate in uterine vascular smooth muscle; this may reflect involvement of systemic type 1 ANG II (AT1) receptor-mediated α-adrenergic activation. To examine this, we compared systemic pressor and UVR responses to intravenous phenylephrine and ANG II without and with systemic or uterine α-receptor blockade and in the absence or presence of AT1 receptor blockade in pregnant and nonpregnant ewes. Systemic α-receptor blockade inhibited phenylephrine-mediated increases in mean arterial pressure (MAP) and UVR, whereas uterine α-receptor blockade alone did not alter pressor responses and resulted in proportionate increases in UVR and MAP. Although neither systemic nor uterine α-receptor blockade affected ANG II-mediated pressor responses, UVR responses decreased >65% and also were proportionate to increases in MAP. Systemic AT1 receptor blockade inhibited all responses to intravenous ANG II. In contrast, uterine AT1 receptor blockade + systemic α-receptor blockade resulted in persistent proportionate increases in MAP and UVR. Uterine AT2 receptor blockade had no effects. We have shown that ANG II-mediated pressor responses reflect activation of systemic vascular AT1 receptors, whereas increases in UVR reflect AT1 receptor-mediated release of an α-agonist and uterine autoregulatory responses.

scholarly journals Thrombin Inhibition Prevents Endothelial Dysfunction and Reverses 20-HETE Overproduction without Affecting Blood Pressure in Angiotensin II-Induced Hypertension in Mice

2021 ◽  
Vol 22 (16) ◽  
pp. 8664
Author(s):  
Agnieszka Kij ◽  
Anna Bar ◽  
Kamil Przyborowski ◽  
Bartosz Proniewski ◽  
Lukasz Mateuszuk ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Ex Vivo ◽  
Wall Thickening ◽  
Ang Ii ◽  
Thrombin Activity ◽  
Induced Hypertension ◽  
No Bioavailability ◽  
Inhibition Of Thrombin

Angiotensin II (Ang II) induces hypertension and endothelial dysfunction, but the involvement of thrombin in these responses is not clear. Here, we assessed the effects of the inhibition of thrombin activity by dabigatran on Ang II-induced hypertension and endothelial dysfunction in mice with a particular focus on NO- and 20-HETE-dependent pathways. As expected, dabigatran administration significantly delayed thrombin generation (CAT assay) in Ang II-treated hypertensive mice, and interestingly, it prevented endothelial dysfunction development, but it did not affect elevated blood pressure nor excessive aortic wall thickening. Dabigatran’s effects on endothelial function in Ang II-treated mice were evidenced by improved NO-dependent relaxation in the aorta in response to acetylcholine in vivo (MRI measurements) and increased systemic NO bioavailability (NO2− quantification) with a concomitant increased ex vivo production of endothelium-derived NO (EPR analysis). Dabigatran treatment also contributed to the reduction in the endothelial expression of pro-inflammatory vWF and ICAM-1. Interestingly, the fall in systemic NO bioavailability in Ang II-treated mice was associated with increased 20-HETE concentration in plasma (UPLC-MS/MS analysis), which was normalised by dabigatran treatment. Taking together, the inhibition of thrombin activity in Ang II-induced hypertension in mice improves the NO-dependent function of vascular endothelium and normalises the 20-HETE-depedent pathway without affecting the blood pressure and vascular remodelling.

Renal and Mesenteric Arterial Tone in Rats with Human Renin and Angiotensinogen Genes

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 694-694
Author(s):  
Eero Ma Mervaala ◽  
Zhong Jiang Cheng ◽  
Ilkka Tikkanen ◽  
Risto Lapatto ◽  
Pekka Rauhala ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Endothelial Dysfunction ◽  
Early Stage ◽  
At1 Receptor ◽  
Receptor Blockade ◽  
Ang Ii ◽  
Down Regulation ◽  
Human Renin ◽  
Cox Inhibitor ◽  
Conduit Vessel

P6 The vascular endothelium plays a key role in the control of vasomotor tone, local hemostasis, and vascular wall proliferation processes. We characterized vascular functions in double-transgenic rats (dTGR) harboring human renin and human angiotensinogen. In dTGR, the endothelium-mediated relaxations of noradrenaline (NA)-precontracted renal (large conduit vessel) and mesenteric arterial (smaller conduit vessel) rings to acetylcholine (ACh) were markedly impaired, compared to normotensive Sprague Dawley rats (p<0.05). In contrast, the endothelium-independent relaxation to sodium nitroprusside (SNP) were similar in both strains. Preincubation of the arterial rings with the NOS inhibitor L-NAME and the COX inhibitor diclofenac inhibited relaxations to ACh almost completely in dTGR, suggesting that endothelial dysfunction could be attributed, at least in part, to reduced relaxation via arterial K+ channels. Contractions to Ang II, ET-1, and NA were decreased in dTGR suggesting agonist-dependent down-regulation of the receptors. The vascular media-to-lumen ratio was similar in both strains, indicating that vascular functions were characterized during an early stage of hypertension. 24-hour urinary NOx excretion, a marker of total body NO generation, was markedly decreased in dTGR (p<0.05). AT1 receptor blockade by valsartan (30 mg/kg p.o. for 3 weeks) normalized blood pressure, endothelial dysfunction, and the contractile responses to ET-1 and NA. We also quantified AT1, AT2, neutral endopeptidase (NEP), and ACE expressions in the kidney by autoradiography. In dTGR, AT1, AT2 and NEP expressions were decreased, whereas ACE expression was unchanged. The activity of renal xanthine oxidoreductase (XOR), a hypoxia-inducible enzyme capable of generating reactive oxygen species, was increased by 50 % in dTGR, and normalized by valsartan. Our findings indicate that hypertension in dTGR is associated with endothelial dysfunction, down-regulation of Ang II, ET-1, and NA receptors, as well as increased renal XOR activity. AT1 receptor blockade effectively normalized blood pressure, alterations in arterial function, and renal XOR activity.

Angiotensin II-induced genomic damage in renal cells can be prevented by angiotensin II type 1 receptor blockage or radical scavenging

2007 ◽  
Vol 292 (5) ◽  
pp. F1427-F1434 ◽  
Author(s):  
Nicole Schupp ◽  
Ursula Schmid ◽  
Przemyslaw Rutkowski ◽  
Ursula Lakner ◽  
Nilesh Kanase ◽  
...  
Keyword(s):  
Dna Damage ◽  
Angiotensin Ii ◽  
Comet Assay ◽  
Kidney Diseases ◽  
Rat Kidney ◽  
Radical Scavenging ◽  
Kidney Cells ◽  
Ang Ii ◽  
Subsequent Formation

Hypertensive patients exhibit elevated cancer incidence, especially of cancers of the kidney. Elevated levels of ANG II, the active peptide of the renin-angiotensin system, regulating blood pressure and cardiovascular homeostasis, are known to cause hypertension and kidney diseases. There is evidence that ANG II is an activator of NAD(P)H oxidase, leading to the formation of free radicals, which are known to participate in the induction of DNA damage. This study was undertaken to characterize ANG II-induced DNA damage. DNA damage was measured by comet assay and micronucleus frequency test. Incubation of pig kidney cells (LLC-PK1) in vitro with ANG II concentrations between 85 and 340 nM led to a 6- to 15-fold increase of DNA damage compared with the control as revealed by comet assay analysis. Micronuclei were induced about fourfold compared with the control in pig and rat kidney cells (LLC-PK1, NRK) and in human promyelocytic cells (HL-60). ANG II-induced DNA damage could be prevented by coincubation with the ANG II type 1 receptor blocker candesartan and the antioxidants N-acetylcysteine and α-tocopherol. The ANG II type 2 receptor antagonist PD123319 could not reduce ANG II-induced DNA damage. Measurement of reactive oxygen species (ROS) by flow cytometry showed an enhanced formation after exposure to ANG II and a reduction of ROS after candesartan, N-acetylcysteine, and α-tocopherol. The present findings support our hypothesis that ANG II causes DNA damage via ANG II type 1 receptor binding and subsequent formation of oxidative stress.

scholarly journals Angiotensin II type 1 receptor blockade to control blood pressure in postmenopausal women: Influence of hormone replacement therapy

2002 ◽  
Vol 62 ◽  
pp. S36-S41 ◽  
Author(s):  
Francisco Fernández-Vega ◽  
José Abellán ◽  
Onofre Vegazo ◽  
Soledad García De Vinuesa ◽  
José Carlos Rodríguez ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Hormone Replacement Therapy ◽  
Angiotensin Ii ◽  
Replacement Therapy ◽  
Postmenopausal Women ◽  
Hormone Replacement ◽  
Receptor Blockade ◽  
Control Blood Pressure

scholarly journals Angiotensin III Stimulates Aldosterone Secretion from Adrenal Gland Partially via Angiotensin II Type 2 Receptor But Not Angiotensin II Type 1 Receptor

Endocrinology ◽  
2011 ◽  
Vol 152 (4) ◽  
pp. 1582-1588 ◽  
Author(s):  
Junichi Yatabe ◽  
Minoru Yoneda ◽  
Midori S. Yatabe ◽  
Tsuyoshi Watanabe ◽  
Robin A. Felder ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Receptor Subtypes ◽  
Ang Ii ◽  
Aldosterone Secretion ◽  
Plasma Aldosterone Concentration ◽  
Ang Iv

Abstract Angiotensin II (Ang II) and Ang III stimulate aldosterone secretion by adrenal glomerulosa, but the angiotensin receptor subtypes involved and the effects of Ang IV and Ang (1–7) are not clear. In vitro, different angiotensins were added to rat adrenal glomerulosa, and aldosterone concentration in the medium was measured. Ang II-induced aldosterone release was blocked (30.3 ± 7.1%) by an Ang II type 2 receptor (AT2R) antagonist, PD123319. Candesartan, an Ang II type 1 receptor (AT1R) antagonist, also blocked Ang II-induced aldosterone release (42.9 ± 4.8%). Coadministration of candesartan and PD123319 almost abolished the Ang II-induced aldosterone release. A selective AT2R agonist, CGP42112, was used to confirm the effects of AT2R. CGP42112 increased aldosterone secretion, which was almost completely inhibited by PD123319. In addition to Ang II, Ang III also induced aldosterone release, which was not blocked by candesartan. However, PD123319 blocked 22.4 ± 10.5% of the Ang III-induced aldosterone secretion. Ang IV and Ang (1–7) did not induce adrenal aldosterone secretion. In vivo, both Ang II and Ang III infusion increased plasma aldosterone concentration, but only Ang II elevated blood pressure. Ang IV and Ang (1–7) infusion did not affect blood pressure or aldosterone concentration. In conclusion, this report showed for the first time that AT2R partially mediates Ang III-induced aldosterone release, but not AT1R. Also, over 60% of Ang III-induced aldosterone release may be independent of both AT1R and AT2R. Ang III and AT2R signaling may have a role in the pathophysiology of aldosterone breakthrough.

Angiotensin II Type 1 Receptor Blockade Improves Hyperglycemia-Induced Endothelial Dysfunction and Reduces Proinflammatory Cytokine Release From Leukocytes

2007 ◽  
Vol 49 (1) ◽  
pp. 6-12 ◽  
Author(s):  
Judith M Willemsen ◽  
Jan W Westerink ◽  
Geesje M Dallinga-Thie ◽  
Anton-Jan van Zonneveld ◽  
Carlo A Gaillard ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Proinflammatory Cytokine ◽  
Receptor Blockade ◽  
Cytokine Release

Abstract 456: Role of Signal Transducer and Activator of Transcription protein (STAT)-1 in the Angiotensin II-induced Cardiovascular Damage

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Stefan Chmielewski ◽  
Cristiane Aoqui ◽  
Hans Bluijssen ◽  
Marcus Baumann
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Mesenteric Arteries ◽  
Ang Ii ◽  
Independent Manner ◽  
Pressure Independent

Background: Inflammation participates importantly in hypertensive organ damage. Angiotensin II (Ang II) plays a crucial role in hypertension and induces inflammation. An essential mediator of inflammation is the transcription factor STAT1 which is activated by interferon but also by Ang II. We hypothesized that activation of STAT1 during Ang II infusion upregulates chemokines, enhances chemotaxis and consequently results in heart fibrosis and vessel dysfunction independent on blood pressure and hypertrophy Methods: C57BL/6, C57BL/6 receiving candesartan (5mg/kg) and STAT1-/- mice received infusion of Ang II 1.5 μg/g/day or placebo for 4 weeks (n=9/group). Blood pressure was measured using tail cuff pletysmography. Expression of chemokines Cxcl10, Cxcl9 and MCP-1 as well as Nos2 were investigated. Small mesenteric arteries (SMA) were mounted in a wire myograph to assess their function. Cardiac hypertrophy and inflammation (CD45 staining) and fibrosis (hydroxyproline assay) were determined. Results: Ang II caused expression of IFNg in C57BL/6 and STAT1-/- in vitro and in vivo. Blood pressure and cardiac hypertrophy did not differ between angiotensin treated C57BL/6 and STAT1-/- mice. Ang II increased in C57BL/6 expression of STAT1 dependent genes of chemokines and Nos2 (Cxcl10: 4.8-fold, Cxcl9: 3.4-fold, MCP-1: 6.6-fold, Nos2: 2.6-fold; all P<0.05) whereas this remained abolished in STAT1-/- mice. Ang II lead in STAT1-/- mice as compared to C57BL/6 to decreased cardiac CD45 number/view (C57BL/6-AngII: 27±4 STAT1-/--AngII: 11±5; P<0.05) and reduced cardiac fibrosis (hydroxyproline assay: C57BL/6-AngII: 80.6±11.8μmol/l versus STAT1-/- -AngII: 55.0±8.4μmol/l; P<0.05). Mesenteric arteries of STAT1-/- mice were fully protected against angiotensin induced endothelial dysfunction. Candesartan (AT1 receptor antagonist) inhibited action of Ang II in C57BL/6 and reduced but not reversed expression of chemokines in the heart. Conclusions: Lack of STAT1 revealed protection against Ang II-induced cardiac fibrosis and endothelial dysfunction. We suggest that STAT1-induced chemokine activation induces chemotaxis into hypertensive target organs and modifies cardiac fibrosis and vascular dysfunction in a blood pressure-independent manner.

Involvement of central angiotensin II type 1 receptors in LPS-induced systemic vasopressin release and blood pressure regulation in rats

2009 ◽  
Vol 106 (6) ◽  
pp. 1943-1948 ◽  
Author(s):  
Fumihiro Shimizu ◽  
Toshihiro Kasai ◽  
Akira Takamata
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Enzyme Inhibitor ◽  
Plasma Osmolality ◽  
Blood Pressure Regulation ◽  
Ang Ii ◽  
Pressure Regulation ◽  
Vasopressin Release ◽  
Captopril Treatment

The purpose of this study was to evaluate the involvement of central angiotensin II (ANG II) and ANG II type 1 (AT1) receptors in systemic release of arginine vasopressin (AVP) and blood pressure regulation during endotoxemia. LPS (150 μg/kg) was injected intravenously 30 min after intracerebroventricular (icv) losartan (50 μg), an AT1 receptor antagonist, or subcutaneous (sc) captopril (50 mg/kg), an angiotensin-converting enzyme inhibitor. Rats with icv and sc saline injections served as control. LPS administration increased plasma AVP concentration from 2.1 ± 0.2 to 15.2 ± 2.5 pg/ml (60 min after LPS injection) without significant changes in plasma osmolality or hematocrit. LPS-induced AVP secretion was significantly attenuated by pretreatment with icv losartan (2.3 ± 0.5 to 3.7 ± 0.5 pg/ml) but was not attenuated after peripheral captopril treatment (2.2 ± 0.6 to 17.6 ± 4.2 pg/ml). LPS administration significantly decreased systolic blood pressure (SBP) by 22.7 ± 5.4 mmHg after intravenous LPS injection in icv losartan-treated rats, while SBP remained unchanged in vehicle-treated or sc captopril-treated rats by intravenous LPS. These results indicate that central AT1 receptors, not responsive to peripheral ANG II, play an important role in systemic AVP secretion and maintenance of blood pressure during endotoxemia.

scholarly journals Soluble (Pro)Renin Receptor Induces Endothelial Dysfunction and Hypertension in Mice with Diet-Induced Obesity via Activation of AngiotensinII Type 1 Receptor

2021 ◽  
Author(s):  
Ziwei Fu ◽  
Fei Wang ◽  
Xiyang Liu ◽  
Jiajia Hu ◽  
Jiahui Su ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Endothelial Dysfunction ◽  
Umbilical Vein ◽  
Elevated Blood Pressure ◽  
H2o2 Production ◽  
No Production ◽  
Ang Ii ◽  
Elevated Blood ◽  
Diet Induced Obesity

Until now, renin-angiotensin system (RAS) hyperactivity was largely thought to result from angiotensin II (Ang II) dependent stimulation of the Ang II type 1 receptor (AT1R). Here we assessed the role of soluble (pro)renin receptor (sPRR), a product of site-1 protease-mediated cleavage of (pro)renin receptor (PRR), as a possible ligand of the AT1R in mediating: (i) endothelial cell dysfunction in vitro; and (ii) arterial dysfunction in mice with diet-induced obesity. Primary human umbilical vein endothelial cells (HUVECs) treated with a recombinant histidine-tagged sPRR (sPRR-His) exhibited IκBα degradation concurrent with NF-κB p65 activation. These responses were secondary to sPRR-His evoked elevations in Nox4-derived H2O2 production that resulted in inflammation, apoptosis and reduced NO production. Each of these sPRR-His-evoked responses was attenuated by AT1R inhibition using Losartan (Los) but not ACE inhibition using captopril (Cap). Further mechanistic exploration revealed that sPRR-His activated AT1R downstream Gq signaling pathway. Immunoprecipitation coupled with autoradiography experiments and radioactive ligand competitive binding assays indicate sPRR directly interacts with AT1R via Lysine199 and Asparagine295. Important translational relevance was provided by findings from obese C57/BL6 mice that sPRR-His evoked endothelial dysfunction was sensitive to Los. Besides, sPRR-His elevated blood pressure in obese C57/BL6 mice, an effect that was reversed by concurrent treatment with Los but not Cap. Collectively, we provide solid evidence that the AT1R mediates the functions of sPRR during obesity-related hypertension. Inhibiting sPRR signaling should be considered further as a potential therapeutic intervention in the treatment and prevention of cardiovascular disorders involving elevated blood pressure.

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