scholarly journals Renal impairment induced by prenatal exposure to angiotensin II in male rat offspring

2019 ◽  
Vol 244 (11) ◽  
pp. 923-931 ◽  
Author(s):  
Pavel Svitok ◽  
Monika Okuliarova ◽  
Ivan Varga ◽  
Michal Zeman
Keyword(s):  
Oxidative Stress ◽  
T Cells ◽  
Angiotensin Ii ◽  
Immune Cells ◽  
Brush Border ◽  
Mature Male ◽  
Proximal Tubules ◽  
Female Rats ◽  
Ang Ii ◽  
Prenatally Exposed

Suboptimal conditions during prenatal ontogeny can impair development of several physiological systems and result in cardiometabolic diseases in adulthood. The kidney has been identified as one of the most sensitive organs for developmental programming, but underlying mechanisms are not fully understood. Therefore, in our study we explored the consequences of prenatally increased angiotensin II (Ang II) on the structural development of the kidney and its damage by infiltrated immune cells under normal diet and after an increased salt intake, as a second insult representing a lifestyle factor in humans. Female rats were implanted with osmotic mini-pumps continuously releasing Ang II of dose 2 µg/kg/h during last two weeks of pregnancy, whereas control females were sham operated. Immunohistological and ultrastructural evaluations of the kidneys and their infiltration with immune cells were performed in mature male progeny kept either on a standard or increased salt (2% NaCl) diet. Glomerular volume decreased and the cortical tubulointerstitial injury increased in the offspring prenatally exposed to Ang II with no additional effect of increased salt. Ultrastructural examination demonstrated degenerative changes in proximal tubules, mainly fewer and shorter microvilli in the brush border, enlarged mitochondria, and an increased number of lysosomes in the epithelial cells in the progeny prenatally exposed to Ang II. Moreover, the treatment resulted in increased infiltration of T-cells and macrophages in the renal cortex compared to controls. These changes paralleled with reduced numbers of cytotoxic T-cells in circulation and higher oxidative burst of neutrophils in the progeny of Ang II-treated mothers compared to controls. Altogether, results suggest that prenatally increased Ang II promoted infiltration of immune cells in the kidney and subsequent oxidative stress, which induced a damage of renal glomerular and tubular system entailing negative consequences on the cardiovascular system. Impact statement Suboptimal prenatal conditions can contribute to development of cardiovascular diseases and an altered renin-angiotensin-aldosterone system (RAAS) can be involved in the process. In our study, increased angiotensin II in pregnant female rats resulted in renal cortical interstitial damage, and renal ultrastructural changes in the glomeruli, the brush border of proximal tubules and mitochondria in mature male offspring. The treatment promoted infiltration of T cells and macrophages in the kidneys and primed an oxidative burst of circulating neutrophils, indicating a pro-inflammatory state in the progeny of angiotensin II-treated mothers. Deregulated RAAS of mothers is involved in developmental programming of hypertension in adult male offspring via damaging kidney morphology and function. These findings suggest that preventing the activation of RAAS and oxidative stress during perinatal development might protect against hypertension development in adult male progeny.

scholarly journals Elevated bone marrow sympathetic drive precedes systemic inflammation in angiotensin II hypertension

2019 ◽  
Vol 317 (2) ◽  
pp. H279-H289 ◽  
Author(s):  
Niousha Ahmari ◽  
Monica M. Santisteban ◽  
Douglas R. Miller ◽  
Natalie M. Geis ◽  
Riley Larkin ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Bone Marrow ◽  
T Cells ◽  
Immune System ◽  
Angiotensin Ii ◽  
Paraventricular Nucleus ◽  
Immune Cells ◽  
Rodent Models ◽  
Ang Ii ◽  
Pressure Infiltration

Increased sympathetic nervous system activity is a hallmark of hypertension (HTN), and it is implicated in altered immune system responses in its pathophysiology. However, the precise mechanisms of neural-immune interaction in HTN remain elusive. We have previously shown an association between elevated sympathetic drive to the bone marrow (BM) and activated BM immune cells in rodent models of HTN. Moreover, microglial-dependent neuroinflammation is also seen in rodent models of HTN. However, the cause-effect relationship between central and systemic inflammatory responses and the sympathetic drive remains unknown. These observations led us to hypothesize that increase in the femoral BM sympathetic nerve activity (fSNA) initiates a cascade of events leading to increase in blood pressure (BP). Here, we investigated the temporal relationship between the BM sympathetic drive, activation of the central and peripheral immune system, and increase in BP in the events leading to established HTN. The present study demonstrates that central infusion of angiotensin II (ANG II) induces early microglial activation in the paraventricular nucleus of hypothalamus, which preceded increase in the fSNA. In turn, activation of fSNA correlated with the timing of increased production and release of CD4+.IL17+ T cells and other proinflammatory cells into circulation and elevation in BP, whereas infiltration of CD4+ cells to the paraventricular nucleus marked establishment of ANG II HTN. This study identifies cellular and molecular mechanisms involved in neural-immune interactions in early and established stages of rodent ANG II HTN. NEW & NOTEWORTHY Early microglia activation in paraventricular nucleus precedes sympathetic activation of the bone marrow. This leads to increased bone marrow immune cells and their release into circulation and an increase in blood pressure. Infiltration of CD4+ T cells into paraventricular nucleus paraventricular nucleus marks late hypertension.

scholarly journals The Effects of Central Angiotensin II and Its Specific Blockers on Nociception. Possible Interactions with Oxidative Stress Status / Efekti Centralnog Angiotenzina II I Njegovih Specifičnih Blokatora Na Nocicepciju. Moguće Interakcije Sa Statusom Oksidativnog Stresa

2013 ◽  
Vol 32 (1) ◽  
pp. 52-58 ◽  
Author(s):  
Oana Arcan ◽  
Alin Ciobica ◽  
Walther Bild ◽  
Bogdan Stoica ◽  
Lucian Hritcu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Analgesic Effect ◽  
Pain Perception ◽  
Ace Inhibitor ◽  
Renin Angiotensin System ◽  
Latency Time ◽  
Ang Ii ◽  
Hot Plate ◽  
At2 Receptors

SummaryIt has already been demonstrated that a complete brain renin-angiotensin system (RAS) exists distinctly separate from the peripheral system and is implicated in complex functions such as memory, emotional responses and pain. Regarding the implications of angiotensin II (the main bioactive peptide of RAS) in pain, although there are many studies in this area of research, most of the results are controversial. Also, it seems that oxidative stress follows angiotensin II infusion, but the role of AT1 vs. AT2 receptors is not well established. In this context, we were interested in studying the effects of central RAS on nociception, through the intracerebroventricular administration of losartan and PD-123177 (antagonists for the AT1/AT2 receptors), as well as an ACE inhibitor (captopril) and also angiotensin II in rats, which were subsequently tested using the hot-plate task, a well known behavioral test for pain perception. We present here the analgesic effect of angiotensin II administration, as shown by in creased latency-time in the hot-plate, as well as a nociceptive effect of angiotensin II blockers like AT1 and AT2 specific antagonists (losartan and PD-123177) and an ACE inhibitor (captopril), as their administration resulted in decreased latency-time. Moreover, we demonstrated a significant correlation between the results of the nociceptive behavioral task and the levels of some main oxidative stress markers. This provides additional evidence for an analgesic effect of Ang II administration, as well as for a nociceptive effect of Ang II blockers. Moreover, a significant correlation between the nociception and angiotensin II-induced oxidative stress is presented.

scholarly journals Proximal Tubule-Specific Deletion of Angiotensin II Type 1a Receptors in the Kidney Attenuates Circulating and Intratubular Angiotensin II–Induced Hypertension in PT- Agtr1a −/− Mice

Hypertension ◽  
2021 ◽  
Author(s):  
Xiao Chun Li ◽  
Ana Paula Oliveira Leite ◽  
Xiaowen Zheng ◽  
Chunling Zhao ◽  
Xu Chen ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Fusion Protein ◽  
Proximal Tubule ◽  
Proximal Tubules ◽  
Normal Blood ◽  
Ang Ii ◽  
Normal Blood Pressure ◽  
Wild Type ◽  
Induced Hypertension

The present study used a novel mouse model with proximal tubule-specific knockout of AT 1a receptors in the kidney, PT- Agtr1a −/− , to test the hypothesis that intratubular Ang II (angiotensin II) and AT 1a receptors in the proximal tubules are required for maintaining normal blood pressure and the development of Ang II–induced hypertension. Twenty-six groups (n=6–15 per group) of adult male wild-type, global Agtr1a −/− , and PT- Agtr1a −/− mice were infused with Ang II (1.5 mg/kg per day, IP), or overexpressed an intracellular Ang II fusion protein in the proximal tubules for 2 weeks. Basal telemetry blood pressure were ≈15±3 mm Hg lower in PT- Agtr1a −/− than wild-type mice and ≈13±3 mm Hg higher than Agtr1a −/− mice ( P <0.01). Basal glomerular filtration was ≈23.9% higher ( P <0.01), whereas fractional proximal tubule Na + reabsorption was lower in PT- Agtr1a −/− mice ( P <0.01). Deletion of AT 1a receptors in the proximal tubules augmented the pressure-natriuresis response ( P <0.01) and natriuretic responses to salt loading or Ang III infusion ( P <0.01). Ang II induced hypertension in wild-type, PT- Agtr1a −/− and PT- Nhe3 −/− mice, but the pressor response was ≈16±2 mm Hg lower in PT- Agtr1a −/− and PT- Nhe3 −/− mice ( P <0.01). Deletion of AT 1a receptors or NHE3 (Na + /H + exchanger 3) in the proximal tubules attenuated ≈50% of Ang II–induced hypertension in wild-type mice ( P <0.01), but blocked intracellular Ang II fusion protein-induced hypertension in PT- Agtr1a −/− mice ( P <0.01). Taken together, the results of the present study provide new insights into the critical role of intratubular Ang II/AT 1 (AT 1a )/NHE3 pathways in the proximal tubules in normal blood pressure control and the development of Ang II–induced hypertension.

Embryonic lethality in Dear gene-deficient mice: new player in angiogenesis

2005 ◽  
Vol 23 (3) ◽  
pp. 257-268 ◽  
Author(s):  
Victoria L. M. Herrera ◽  
Lorenz R. B. Ponce ◽  
Pia D. Bagamasbad ◽  
Benjamin D. VanPelt ◽  
Tamara Didishvili ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Embryonic Lethality ◽  
Female Rats ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Angiotensin Ii Receptor ◽  
Endothelin 1 ◽  
Receptor Isoforms ◽  
Age Range ◽  
Deficient Mice

The dual endothelin-1/angiotensin II receptor (Dear) binds endothelin-1 (ET-1) and angiotensin II (ANG II) with equal affinities in the Dahl S/JRHS rat strain. To elucidate its physiological significance within the context of multiple receptor isoforms and diverse ET-1 and ANG II functions spanning blood pressure regulation, tumor proliferation, and angiogenesis, we characterized mouse Dear and Dear-deficient mice. Unlike null mutant models of ET-1, ANG II, and all other ET-1 and ANG II receptors, Dear−/− deficiency results in impaired angiogenesis, dysregulated neuroepithelial development, and embryonic lethality by embryonic day 12.5. Interestingly, mouse Dear does not bind ANG II, similar to Dahl R/JRHS rat Dear, but binds ET-1 and vascular endothelial growth factor (VEGF) signal peptide (VEGFsp) with equal affinities, suggesting a putative novel multifunction for VEGFsp and a parsimonious mechanism for coordination of VEGF-induced and Dear-mediated pathways. Consistent with its developmental angiogenic role, Dear inhibition results in decreased tumor growth in B16-F10 melanoma cell-induced subcutaneous tumor in female Dear+/−/C57BL6BC10 mice, but not in males (age 3.5 mo), and in 127Cs radiation-induced orthotopic mammary tumors in Sprague-Dawley female rats (age range 3–6.5 mo). Altogether, the data identify Dear as a new player in angiogenesis during development downstream to, and nonredundant with, VEGF-mediated pathways, as well as a putative modulator of tumor angiogenesis acting within a gender-specific paradigm.

Abstract 1374: A Novel eNOS-Independent Protective Action of Statin against Angiotensin II-Induced Atrial Remodeling Via Attenuating Rac-1-Mediated Oxidative Stress

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Shusuke Yagi ◽  
Masashi Akaike ◽  
Ken-ichi Aihara ◽  
Kazue Ishikawa ◽  
Takayuki Ise ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Left Atrial ◽  
Protective Action ◽  
Left Atrial Volume ◽  
Cardiomyocyte Hypertrophy ◽  
Radical Scavenger ◽  
Atrial Remodeling ◽  
Ang Ii ◽  
Anticoagulation Agents

Activation of the renin-angiotensin system exacerbates atrial remodeling, leading to atrial fibrillation (AF) and thrombosis, especially in a condition with decreased nitric oxide bioavailability. Although antiarrhythmic and anticoagulation agents are used under these pathological conditions, these drugs are not able to ameliorate atrial remodeling. Recently, it has been reported that statins reduce the incidence of AF through attenuating atrial remodeling; however, the mechanisms have not been completely elucidated. This study was designed to determine the beneficial effect of pitavastatin (Pit) against angiotensin II (Ang II)-induced atrial remodeling and to elucidate its mechanism. eNOS knockout mice were sham-operated or infused with Ang II by an osmotic mini-pump for 2 weeks, and Ang II-infused mice were divided into 3 treatment groups: Pit, tempol, a free radical scavenger, or a vehicle. Echocardiography and electrocardiography showed that Ang II infusion increased left atrial volume and caused a high incidence of AF, whereas Pit and tempol treatment prevented Ang II-induced left atrial enlargement and AF. Histological analysis showed that acceleration of Ang II-induced interstitial fibrosis, perivascular fibrosis and cardiomyocyte hypertrophy in the atrium were all attenuated by Pit and tempol treatment. Immunohistochemistry showed that Ang II down-regulated thrombomodulin and up-regulated tissue factor and plasminogen activator inhibitor-1 in the left atrium and that Pit and tempol treatment corrected the Ang II-induced thrombogenic condition. Moreover, Pit and tempol reduced Ang II-induced atrial superoxide production, detected by dihydroethidium staining, and atrial TGF- β 1 expression and Smad 2/3 phosphorylation. Activity of Rac-1-GTPase involved in the activation of NADPH oxidase in the atrium was attenuated by Pit but not by tempol. Pit exerts eNOS-independent protective actions against Ang II-induced atrial structural and electrical remodeling with enhanced thrombogenicity through suppressing Rac-1-mediated oxidative stress, leading to suppression of the TGF- β 1/Smad pathway.

Abstract 1476: Angiotensin II Induced Hypertrophic Response And Oxidative Stress Is Attenuated In Mice Lacking The Gene For Tnf-α

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Srinivas Sriramula ◽  
Nithya Mariappan ◽  
Elizabeth McILwain ◽  
Joseph Francis
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Collagen Type ◽  
Resonance Spectroscopy ◽  
Type I ◽  
Ang Ii ◽  
Hypertrophic Response ◽  
Tnf Α ◽  
And Oxidative Stress

Tumor necrosis factor-alpha (TNF-α) and angiotensin II (Ang II) play an important role in the pathophysiology of cardiovascular disease in part by inducing the cardiac hypertrophic response and oxidative stress. Recently we demonstrated that angiotensin induced hypertensive response is attenuated in mice lacking the gene for TNF-α. In this study, we examined whether Ang II induced cardiac hypertrophy and increased oxidative stress is mediated through TNF-α. Methods and results: Male TNF-α (−/−) and age matched control (WT) mice were subcutaneously implanted with osmotic minipumps containing Ang II (1 μg/kg/min) or saline for 14 days. Human recombinant TNF-α was injected in one group of TNF-α (−/−) mice (10 μg/kg/day) for 14 days. In WT+Ang mice, a temporal increase in blood pressure was observed during the study as measured by radio telemetry transmitters. At the end of the study, echocardiography revealed an increase in thickness and dimensions of left ventricle (LV) and decreased fractional shortening (%FS) in WT+Ang mice. Real time RT-PCR showed that Ang II- infusion resulted in an increase in heart/bodyweight ratio and of cardiac hypertrophy markers ANP and BNP, and profibrotic genes Collagen Type I, Collagen Type II, and TGF-β in WT mice. Electron Spin resonance spectroscopy revealed an increase in total ROS, superoxide and peroxynitrite in the WT+ANG mice when compared to control WT mice. However, these changes were all attenuated in TNF-α (−/−)+Ang mice. Ang II infusion also increased significantly the mRNA expression of gp91Phox, NOX-1, NOX-4 and AT1R in the LV of WT mice, but not in TNF-α (−/−) mice. Interestingly, injection of TNF-α in the TNF-α (−/−) mice, treated with Ang II resulted in increased cardiac hypertrophy and oxidative stress. Conclusions: Findings from the present study suggest that TNF-α plays an important role in the development of cardiac hypertrophy and oxidative stress in Ang II-induced hypertension.

Abstract 1380: Antioxidants Decrease Neuronal Angiotensin II Type 1 Receptor in Heart Failure: Inhibition of Activator Protein 1 and Jun N-Terminal Kinase

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Dongmei Liu ◽  
Lie Gao ◽  
Kurtis G Cornish ◽  
Irving H Zucker
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Angiotensin Ii ◽  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Neuronal Cell ◽  
Activator Protein 1 ◽  
Ang Ii ◽  
Nadph Oxidase Activity ◽  
Activator Protein

In a previous study, we showed that Ang II type I receptor (AT1R) expression increased in the rostral ventrolateral medulla (RVLM) of chronic heart failure (CHF) rabbits and in normal rabbits infused with intracerebroventricular (ICV) Angiotensin II (AngII). The present study investigated if oxidative stress plays a role in Ang II induced AT1R upregulation and its relationship to the transcription factor activator protein 1 (AP1) in CHF rabbits and in the CATHa neuronal cell line. In neuronal cell cultures, Ang II significantly increased AT1R mRNA by 153 ± 22%, P <0.01; c-Jun mRNA by 90 ± 10%, P < 0.01; NADPH oxidase activity by 126 ± 43%, P < 0.01 versus untreated cells; Tempol, Apocynin and the AP 1 inhibitor Tanshinone II reversed the increased AT1R, c-Jun expression and NADPH oxidase activity induced by AngII. We examined the effect of ICV Tempol on expression of these proteins in the RVLM of CHF rabbits. Compared to untreated CHF rabbits Tempol significantly decreased AT1R protein expression (0.88±0.16 vs. 1.6±0.29, P <0.05), phosphorylated Jnk protein (0.10±0.02 vs. 0.31±0.10, P <0.05), and phosphorylated c-Jun (0.02±0.001 vs. 0.14±0.05, P <0.05). These data suggest that Ang II induces AT1R upregulation at the transcriptional level by activation of oxidative stress and AP1 in both cultured cells and in intact brain. Antioxidant agents may be beneficial in CHF by decreasing AT1R expression through the Jnk and AP1 pathway.

Abstract 065: Overexpression of an Intracellular Angiotensin II Fusion Protein Selectively in the Mitochondria of the Proximal Tubules Elevates Blood Pressure in Mice via AT 1a Receptor-mediated Mitochondrial Respiratory and Glycolysis Stress

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Xiao C Li ◽  
Manoocher Soleimani ◽  
Hoang Nguyen ◽  
Hong Li ◽  
Jia L Zhuo
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Fusion Protein ◽  
Proximal Tubule ◽  
Physiological Role ◽  
Proximal Tubules ◽  
Ang Ii ◽  
Stress Tests ◽  
Arterial Blood ◽  
Mitochondrial Respiratory

An intracrine mitochondrial renin-angiotensin system (RAS) has recently been identified in various animal and human tissues, but whether the mitochondrial RAS plays a physiological role in the regulation of blood pressure remains unknown. The present study tested whether overexpression of an intracellular angiotensin II fusion protein, ECFP/ANG II, selectively in the mitochondria of the proximal tubules alters blood pressure, and whether the effects may involve AT 1a receptors and the Na + /H + exchanger 3 (NHE3). An adenoviral vector encoding ECFP/ANG II, a mitochondria targeting sequence, and the sglt2 promoter, Ad-sglt2-mito-ECFP/ANG II, was constructed for proximal tubule- and mitochondria-specific overexpression for 2 weeks. In adult male C57BL/6J mice, overexpression of mito-ECFP/ANG II in the mitochondria of the proximal tubules increased systolic blood pressure (SBP) significantly (Control: 116 ± 3 vs. mito-ECFP/ANG II: 128 ± 3 mmHg; p <0.01, n=15). The blood pressure-increasing effect of Ad-sglt2-mito-ECFP/ANG II was blocked in proximal tubule-specific AT 1a -KO mice (Control: 105 ± 2 vs. mito-ECFP/ANG II: 104 ± 4 mmHg; n.s ., n=7), or in proximal tubule-specific NHE3-KO mice (Control: 108 ± 3 vs. mito-ECFP/ANG II: 107 ± 3 mmHg; n.s ., n=13), respectively. In further experiments, mouse proximal tubule cells were transfected with Ad-sglt2-mito-ECFP/ANG II for 48 h and treated with the AT 1 blocker losartan (10 μM) or the AT 2 blocker PD123319 (10 μM) to measure mitochondrial respiratory and glycolytic function using Seahorse XF Cell Mito and XF Glycolysis Stress Tests. The mito-ECFP/ANG II expression was robust and colocalized with MitoTracker® Red FM. Overexpression of mito-ECFP/ANG II markedly increased oxygen consumption rate (OCR) (Control: 139.4 ± 9.2 vs. mito-ECFP/ANG II: 236.3 ± 12.6 pmol/min; p <0.01, n=12) and extracellular acidification rate (ECAR) (Control: 8.8 ± 0.6 vs. mito-ECFP/ANG II: 11.8 ± 1.2 mpH/min; p <0.01, n=12), respectively. Losartan blocked the effects of mito-ECFP/ANG II on OCR and ECAR, whereas PD123319 had no effect. We conclude that intracellular ANG II may activate AT 1 receptors in the mitochondria of the proximal tubules to alter mitochondrial respiratory and glycolytic function and arterial blood pressure.

Abstract 598: Deletion of Microsomal PGE Synthase-1 Decreases Oxidative Stress and Protects Against Abdominal Aortic Aneurysm Formation in Angiotensin II-Infused Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Miao Wang ◽  
Jane Stubbe ◽  
Eric Lee ◽  
Wenliang Song ◽  
Emanuela Ricciotti ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Aortic Aneurysms ◽  
Ang Ii ◽  
Abdominal Aortic ◽  
Density Lipoprotein Receptor ◽  
The Impact

Microsomal (m) prostaglandin (PG) E 2 synthase(S)-1, an enzyme that catalyzes the isomerization of the cyclooxygenase (COX) product, PGH 2 , into PGE 2 , is a major source of PGE 2 in vivo . mPGES-1 deletion in mice was found to modulate experimentally evoked pain and inflammation and atherogenesis is retarded in mPGES-1 knockout (KO) mice. The impact of mPGES-1 deletion on formation of angiotensin II (Ang II)-induced abdominal aortic aneurysms (AAA) was studied in mice lacking the low density lipoprotein receptor (LDLR −/− ). AngII infusion increased aortic macrophage recruitment and nitrotyrosine staining while upregulating both mPGES-1 and COX-2 and urinary excretion of the major metabolite of PGE 2 (PGE-M). Deletion of mPGES-1 decreased both the incidence and severity of AAA and depressed excretion of both PGE-M and 8, 12-iso-iPF 2a -VI, which reflects lipid peroxidation in vivo . While Ang II infusion augmented prostaglandin biosynthesis, deletion of mPGES-1 resulted in rediversion to PGD 2 , reflected by its major urinary metabolite. However, deletion of the PGD 2 receptor, DP1, did not affect AAA in Ang II infused LDLR −/− mice. These observations indicate that deletion of mPGES-1 protects against AAA formation by AngII in hyperlipidemic mice, perhaps by decreasing oxidative stress. Inhibition of mPGES-1 may represent an effective treatment to limit aneurysm occurrence and expansion.

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