Macrophage 12(S)-HETE Enhances Angiotensin II–Induced Contraction by a BLT2 (Leukotriene B 4 Type-2 Receptor) and TP (Thromboxane Receptor)-Mediated Mechanism in Murine Arteries

12/15-LO (12/15-lipoxygenase), encoded by Alox15 gene, metabolizes arachidonic acid to 12(S)-HETE (12-HETE). Macrophages are the major source of 12/15-LO among immune cells, and 12/15-LO plays a crucial role in development of hypertension. Global Alox15- or macrophage-deficient mice are resistant to Ang II (angiotensin II)–induced hypertension. This study tests the hypothesis that macrophage 12(S)-HETE contributes to Ang II–mediated arterial constriction and thus to development of Ang II–induced hypertension. Ang II constricted isolated abdominal aortic and mesenteric arterial rings. 12(S)-HETE (100 nmol/L) alone was without effect; however, it significantly enhanced Ang II–induced constriction. The presence of wild-type macrophages also enhanced the Ang II–induced constriction, while Alox15 −/− macrophages did not. Using this model, pretreatment of aortic rings with inhibitors, receptor agonists/antagonists, or removal of the endothelium, systematically uncovered an endothelium-mediated, Ang II receptor-2–mediated and superoxide-mediated enhancing effect of 12(S)-HETE on Ang II constrictions. The role of superoxide was confirmed using aortas from p47 phox−/− mice where 12(S)-HETE failed to enhance constriction to Ang II. In cultured arterial endothelial cells, 12(S)-HETE increased the production of superoxide, and 12(S)-HETE or Ang II increased the production of an isothromboxane-like metabolite. A TP (thromboxane receptor) antagonist inhibited 12(S)-HETE enhancement of Ang II constriction. Both Ang II–induced hypertension and the enhancing effect of 12(S)-HETE on Ang II contractions were eliminated by a BLT2 (leukotriene B 4 receptor-2) antagonist. These results outline a mechanism where the macrophage 12/15-LO pathway enhances the action of Ang II. 12(S)-HETE, acting on the BLT2, contributes to the hypertensive action of Ang II in part by promoting endothelial synthesis of a superoxide-derived TP agonist.

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Genetic and genomic evidence for an important role of the Na+/H+ exchanger 3 in blood pressure regulation and angiotensin II-induced hypertension

Physiological Genomics ◽

10.1152/physiolgenomics.00122.2018 ◽

2019 ◽

Vol 51 (4) ◽

pp. 97-108 ◽

Cited By ~ 3

Author(s):

Xiao C. Li ◽

Xiaowen Zheng ◽

Xu Chen ◽

Chunling Zhao ◽

Dongmin Zhu ◽

...

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Proximal Tubule ◽

Proximal Tubules ◽

Ang Ii ◽

Pressure Regulation ◽

Blood Pressure Homeostasis ◽

Induced Hypertension ◽

Basal Blood Pressure

The sodium (Na+)/hydrogen (H+) exchanger 3 (NHE3) and sodium-potassium adenosine triphosphatase (Na+/K+-ATPase) are two of the most important Na+ transporters in the proximal tubules of the kidney. On the apical membrane side, NHE3 primarily mediates the entry of Na+ into and the exit of H+ from the proximal tubules, directly and indirectly being responsible for reabsorbing ~50% of filtered Na+ in the proximal tubules of the kidney. On the basolateral membrane side, Na+/K+-ATPase serves as a powerful engine driving Na+ out of, while pumping K+ into the proximal tubules against their concentration gradients. While the roles of NHE3 and Na+/K+-ATPase in proximal tubular Na+ transport under in vitro conditions are well recognized, their respective contributions to the basal blood pressure regulation and angiotensin II (ANG II)-induced hypertension remain poorly understood. Recently, we have been fortunate to be able to use genetically modified mouse models with global, kidney- or proximal tubule-specific deletion of NHE3 to directly determine the cause and effect relationship between NHE3, basal blood pressure homeostasis, and ANG II-induced hypertension at the whole body, kidney and/or proximal tubule levels. The purpose of this article is to review the genetic and genomic evidence for an important role of NHE3 with a focus in the regulation of basal blood pressure and ANG II-induced hypertension, as we learned from studies using global, kidney- or proximal tubule-specific NHE3 knockout mice. We hypothesize that NHE3 in the proximal tubules is necessary for maintaining basal blood pressure homeostasis and the development of ANG II-induced hypertension.

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Abstract 101: Cardiac Deleterious Role of Galectin-3 in Chronic Angiotensin-II Induced Hypertension

Hypertension ◽

10.1161/hyp.62.suppl_1.a101 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Germán E González ◽

Nour-Eddine Rhaleb ◽

Xiao- P Yang ◽

Oscar A Carretero

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Cardiac Fibrosis ◽

Systolic Dysfunction ◽

Left Ventricular ◽

Carbohydrate Binding ◽

Ang Ii ◽

Induced Hypertension ◽

Galectin 3

We previously described that chronic infusion with Angiotensin II (Ang II) increases cardiac Galectin-3 (Gal-3) expression, a carbohydrate-binding lectin present on macrophages. Also, Gal-3 was proposed to be a powerful predictor for mortality in patients with heart failure. Nevertheless, the role of Gal-3 in the pathogenesis of end organ damage (EOD) in hypertension is unknown. Here, we hypothesized that in Ang II-induced hypertension, genetic deletion of Gal-3 prevents innate immunity, EOD, and left ventricular (LV) dysfunction. Male C57 and Gal-3 KO mice were infused with vehicle (V) or Ang II (90 ng/min; s.c.) for 8 weeks and divided into: 1) C57 + V; 2) Gal-3 KO + V; 3) C57 + Ang II and 4) Gal-3 KO + Ang II. Systolic blood pressure (SBP) was measured by plestimography weekly. At 8 week, we evaluated 1) LV ejection fraction (EF) by echocardiography; 2) cardiac hypertrophy by LV weight/tibia length; 3) cardiac fibrosis by picrosirius red staining; 4) infiltrated macrophages by CD68+ staining; 5) ICAM-1 protein expression by Western blot; and 6) serum interleukin (IL)-6 by ELISA. We found that despite a similar increase in SBP and LV hypertrophy in both strains on Ang II, Gal-3 KO mice had better reserved EF and decreased inflammatory and fibrotic responses (see Table). Results: (MEAN ± SEM at 8 w) *p<0.05 C57+Ang II and Gal-3 KO+Ang II vs C57+V; ‡ p<0.05 Gal-3 KO+Ang II vs C57+Ang II. Conclusion: In Ang II-induced hypertension, deletion of Gal-3 prevents EOD and LV systolic dysfunction without altering blood pressure and LV hypertrophy. This study indicates that the deleterious effects of Ang II could be in part mediated by Gal-3, which enhanced inflammation and fibrosis.

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Peroxisome Proliferator Activated Receptor-αAgonist Slows the Progression of Hypertension, Attenuates Plasma Interleukin-6 Levels and Renal Inflammatory Markers in Angiotensin II Infused Mice

PPAR Research ◽

10.1155/2012/645969 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 12

Author(s):

Justin L. Wilson ◽

Rong Duan ◽

Ahmed El-Marakby ◽

Abdulmohsin Alhashim ◽

Dexter L. Lee

Keyword(s):

Angiotensin Ii ◽

Inflammatory Markers ◽

Peroxisome Proliferator ◽

Ang Ii ◽

Peroxisome Proliferator Activated Receptor ◽

Induced Hypertension ◽

Cox 2 ◽

Anti Inflammatory ◽

Renal Expression

The anti-inflammatory properties of PPAR-αplays an important role in attenuating hypertension. The current study determines the anti-hypertensive and anti-inflammatory role of PPAR-αagonist during a slow-pressor dose of Ang II (400 ng/kg/min). Ten to twelve week old male PPAR-αKO mice and their WT controls were implanted with telemetry devices and infused with Ang II for 12 days. On day 12 of Ang II infusion, MAP was elevated in PPAR-αKO mice compared to WT (161±4 mmHg versus145±4 mmHg) and fenofibrate (145 mg/kg/day) reduced MAP in WT + Ang II mice (134±7 mmHg). Plasma IL-6 levels were higher in PPAR-αKO mice on day 12 of Ang II infusion (30±4versus8±2 pg/mL) and fenofibrate reduced plasma IL-6 in Ang II-treated WT mice (10±3 pg/mL). Fenofibrate increased renal expression of CYP4A, restored renal CYP2J expression, reduced the elevation in renal ICAM-1, MCP-1 and COX-2 in WT + Ang II mice. Our results demonstrate that activation of PPAR-αattenuates Ang II-induced hypertension through up-regulation of CYP4A and CYP2J and an attenuation of inflammatory markers such as plasma IL-6, renal MCP-1, renal expression of ICAM-1 and COX-2.

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Collecting duct (pro)renin receptor targets ENaC to mediate angiotensin II-induced hypertension

AJP Renal Physiology ◽

10.1152/ajprenal.00178.2016 ◽

2017 ◽

Vol 312 (2) ◽

pp. F245-F253 ◽

Cited By ~ 31

Author(s):

Kexin Peng ◽

Xiaohan Lu ◽

Fei Wang ◽

Adam Nau ◽

Ren Chen ◽

...

Keyword(s):

Angiotensin Ii ◽

Protein Expression ◽

Mrna Expression ◽

Collecting Duct ◽

Underlying Mechanism ◽

Ang Ii ◽

Induced Hypertension ◽

Mrna And Protein Expression ◽

Receptor Targets

The (pro)renin receptor (PRR) is abundantly expressed in the collecting duct (CD) and the expression is further induced by angiotensin II (ANG II). The present study was conducted to investigate the role of CD PRR during ANG II-induced hypertension and to further explore the underlying mechanism. Radiotelemetry demonstrated that a 1-wk ANG II infusion gradually and significantly induced hypertensive response in floxed mice and this response was significantly attenuated in mice lacking PRR in the CD (termed CD PRR KO). ANG II infusion in floxed mice increased urinary renin activity and selectively induced renal medullary α-epithelial sodium channel (α-ENaC) mRNA and protein expression, all of which were blunted in the null mice. In cultured mpkCCD cells grown in Transwells, transepithelial Na+ transport as measured by using a volt-ohmmeter was transiently stimulated by acute ANG II treatment, which was abolished by a PRR antagonist, PRO20. In a chronic setting, ANG II treatment induced α-ENaC mRNA expression in mpkCCD cells, which was similarly blocked by PRO20. Chronic intramedullary infusion of an ENaC inhibitor amiloride in rats significantly attenuated ANG II-induced hypertension. Overall, the present study suggests that CD PRR contributes to ANG II-induced hypertension at least partially via activation of renal medullary ENaC.

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Reduced Nhe1 (Na + -H + Exchanger-1) Function Protects ApoE-Deficient Mice From Ang II (Angiotensin II)–Induced Abdominal Aortic Aneurysms

Hypertension ◽

10.1161/hypertensionaha.119.14485 ◽

2020 ◽

Vol 76 (1) ◽

pp. 87-100

Author(s):

Cong-Lin Liu ◽

Xin Liu ◽

Yunzhe Wang ◽

Zhiyong Deng ◽

Tianxiao Liu ◽

...

Keyword(s):

Angiotensin Ii ◽

Cell Apoptosis ◽

Near Infrared ◽

Gelatin Zymography ◽

Aortic Aneurysms ◽

Ang Ii ◽

Abdominal Aortic ◽

Ige Mediated ◽

Human And Mouse

IgE-mediated activation of Nhe1 (Na + -H + exchanger-1) induces aortic cell extracellular acidification and promotes cell apoptosis. A pH-sensitive probe pHrodo identified acidic regions at positions of macrophage accumulation, IgE expression, and cell apoptosis in human and mouse abdominal aortic aneurysm (AAA) lesions. Ang II (angiotensin II)–induced AAA in Nhe1-insufficient Apoe −/− Nhe1 +/− mice and Apoe −/− Nhe1 +/+ littermates tested Nhe1 activity in experimental AAA, because Nhe1 −/− mice develop ataxia and epileptic-like seizures and die early. Nhe1 insufficiency reduced AAA incidence and size, lesion macrophage and T-cell accumulation, collagen deposition, elastin fragmentation, cell apoptosis, smooth muscle cell loss, and MMP (matrix metalloproteinase) activity. Nhe1 insufficiency also reduced blood pressure and the plasma apoptosis marker TCTP (translationally controlled tumor protein) but did not affect plasma IgE. While pHrodo localized the acidic regions to macrophage clusters, IgE expression, and cell apoptosis in AAA lesions from Apoe −/− Nhe1 +/+ mice, such acidic areas were much smaller in lesions from Apoe −/− Nhe1 +/− mice. Nhe1-FcεR1 colocalization in macrophages from AAA lesions support a role of IgE-mediated Nhe1 activation. Gelatin zymography, immunoblot, and real-time polymerase chain reaction analyses demonstrated that Nhe1 insufficiency reduced the MMP activity, cysteinyl cathepsin expression, IgE-induced apoptosis, and NF-κB activation in macrophages and blocked IgE-induced adhesion molecule expression in endothelial cells. A near-infrared fluorescent probe (LS662) together with fluorescence reflectance imaging of intact aortas showed reduced acidity in AAA lesions from Nhe-1-insufficient mice. This study revealed extracellular acidity at regions rich in macrophages, IgE expression, and cell apoptosis in human and mouse AAA lesions and established a direct role of Nhe1 in AAA pathogenesis.

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Reduced expression of SKCa and IKCa channel proteins in rat small mesenteric arteries during angiotensin II-induced hypertension

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00949.2006 ◽

2007 ◽

Vol 292 (5) ◽

pp. H2275-H2284 ◽

Cited By ~ 52

Author(s):

Rob H. P. Hilgers ◽

R. Clinton Webb

Keyword(s):

Angiotensin Ii ◽

Channel Blocker ◽

Mesenteric Arteries ◽

Ang Ii ◽

Expression Levels ◽

Protein Levels ◽

Channel Proteins ◽

Induced Hypertension ◽

Relaxation Responses

Ca2+-activated K+ channels (KCa), in particular, the small and intermediate KCa (SKCa and IKCa, respectively) channels, are key players in endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation in small arteries. Hypertension is characterized by an endothelial dysfunction, possibly via reduced EDHF release and/or function. We hypothesize that during angiotensin II (14 days)-induced hypertension (ANG II-14d), the contribution of SKCa and IKCa channels in ACh-induced relaxations is reduced due to decreased expression of SKCa and IKCa channel proteins in rat small mesenteric arteries (MAs). Nitric oxide- and prostacyclin-independent vasorelaxation to ACh was similar in small MAs of sham-operated and ANG II-14d rats. Catalase had no inhibitory effects on these relaxations. The highly selective SKCa channel blocker UCL-1684 almost completely blocked these responses in MAs of sham-operated rats but partially in MAs of ANG II-14d rats. These changes were pressure dependent since UCL-1684 caused a greater inhibition in MAs of 1-day ANG II-treated normotensive rats compared with ANG II-14d rats. Expression levels of both mRNA and protein SK3 were significantly reduced in MAs of ANG II-14d rats. The IKCa channel blocker 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34) resulted in comparable reductions in the relaxation responses to ACh in MAs of sham-operated and ANG II-14d rats. Relative mRNA expression levels of IK1 were significantly reduced in MAs of ANG II-14d rats, whereas protein levels of IK1 were not but tended to be lower in MAs of ANG II-14d rats. The findings demonstrate that EDHF-like responses are not compromised in a situation of reduced functional activity and expression of SK3 channels in small MAs of ANG II-induced hypertensive rats. The role of IK1 channels is less clear but might compensate for reduced SK3 activity.

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Inhibition of Peptidyl Arginine Deiminase 4-Dependent Neutrophil Extracellular Trap Formation Reduces Angiotensin II-Induced Abdominal Aortic Aneurysm Rupture in Mice

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.676612 ◽

2021 ◽

Vol 8 ◽

Author(s):

Ming Wei ◽

Xia Wang ◽

Yanting Song ◽

Di Zhu ◽

Dan Qi ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

Angiotensin Ii ◽

Aortic Aneurysm ◽

Tissue Injury ◽

Arginine Deiminase ◽

Tunel Staining ◽

Ang Ii ◽

Elastin Degradation ◽

Abdominal Aortic

Objective: Neutrophil infiltration plays an important role in the initiation and development of abdominal aortic aneurysm (AAA). Recent studies suggested that neutrophils could release neutrophil extracellular traps (NETs), leading to tissue injury in cardiovascular diseases. However, the role of NETs in AAA is elusive. This study aimed to investigate the role and underlying mechanism of NETs in AAA development.Methods and Results: An angiotensin II (Ang II) infusion-induced AAA model was established to investigate the role of NETs during AAA development. Immunofluorescence staining showed that citrullinated histone 3 (citH3), myeloperoxidase (MPO), and neutrophil elastase (NE) (NET marker) expressions were significantly increased in Ang II-infused ApoE−/− mice. The circulating double-stranded DNA (dsDNA) level was also elevated, indicating the increased NET formation during AAA. PAD4 inhibitor YW3-56 inhibited Ang II-induced NET formation. Disruption of NET formation by YW3-56 markedly reduced Ang II-induced AAA rupture, as revealed by decreased aortic diameter, vascular smooth muscle cell (VSMC) apoptosis, and elastin degradation. Apoptosis of VSMC was evaluated by TUNEL staining and Annexin V-FITC/PI staining through flow cytometry. Western blot and inhibition experiments revealed that NETs induced VSMC apoptosis via p38/JNK pathway, indicating that PAD4-dependent NET formation played an important role in AAA.Conclusions: This study suggests that PAD4-dependent NET formation is critical for AAA rupture, which provides a novel potential therapeutic strategy for AAA disease.

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Testosterone Metabolite 6β‐Hydroxytestosterone Contributes to Angiotensin II‐Induced Abdominal Aortic Aneurysms in Apoe –/– Male Mice

Journal of the American Heart Association ◽

10.1161/jaha.120.018536 ◽

2021 ◽

Author(s):

Kamalika Mukherjee ◽

Ajeeth K. Pingili ◽

Purnima Singh ◽

Ahmad N. Dhodi ◽

Shubha R. Dutta ◽

...

Keyword(s):

Cytochrome P450 ◽

Risk Factor ◽

Angiotensin Ii ◽

Abdominal Aortic Aneurysms ◽

Aortic Aneurysms ◽

Ang Ii ◽

Male Mice ◽

Cytochrome P450 1B1 ◽

Abdominal Aortic ◽

Induced Hypertension

Background Sex is a prominent risk factor for abdominal aortic aneurysms (AAAs), and angiotensin II (Ang II) induces AAA formation to a greater degree in male than in female mice. We previously reported that cytochrome P450 1B1 contributes to the development of hypertension, as well as AAAs, in male mice. We also found that a cytochrome P450 1B1‐generated metabolite of testosterone, 6β‐hydroxytestosterone (6β‐OHT), contributes to Ang II‐induced hypertension and associated cardiovascular and renal pathogenesis in male mice. The current study was conducted to determine the contribution of 6β‐OHT to Ang II‐induced AAA development in Apoe –/– male mice. Methods and Results Intact or castrated Apoe –/– /Cyp1b1 +/+ and Apoe –/– /Cyp1b1 –/– male mice were infused with Ang II or its vehicle for 28 days, and administered 6β‐OHT every third day for the duration of the experiment. Abdominal aortas were then evaluated for development of AAAs. We observed a significant increase in the incidence and severity of AAAs in intact Ang II‐infused Apoe –/– /Cyp1b1 +/+ mice, compared with vehicle‐treated mice, which were minimized in castrated Apoe –/– /Cyp1b1 +/+ and intact Apoe –/– /Cyp1b1 –/– mice infused with Ang II. Treatment with 6β‐OHT significantly restored the incidence and severity of AAAs in Ang II‐infused castrated Apoe –/– /Cyp1b1 +/+ and intact Apoe –/– /Cyp1b1 –/– mice. However, administration of testosterone failed to increase AAA incidence and severity in Ang II‐infused intact Apoe –/– /Cyp1b1 –/– mice. Conclusions Our results indicate that the testosterone‐cytochrome P450 1B1‐generated metabolite 6β‐OHT contributes to Ang II‐induced AAA development in Apoe –/– male mice.

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