The angiotensin II receptor type 2 agonist CGP 42112A stimulates NO production in the porcine jejunal mucosa

Ewert, Sara; Laesser, Mats; Johansson, B.; Holm, Mathias; Åneman, Anders; Fändriks, Lars

doi:10.1186/1471-2210-3-2

Cited by 21 publications

(7 citation statements)

References 28 publications

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“…In human pulmonary microvascular endothelial cells (HPMEC), Agtr2 mRNA was not detected under normal conditions or in response to LPS injury ( Li et al, 2015 ), while Agtr1 mRNA was increased after LPS. While AT2R-agonists, specifically Compound 21, and to a lesser extent CGP42112, have been reported to confer beneficial effects in ex vivo and in vivo models ( Ewert et al, 2003 ; Bosnyak et al, 2010 ; Rehman et al, 2012 ; Sampson et al, 2016 ), there have been no reports of either AT2R agonist having the ability to augment AT2R expression levels either at the mRNA or protein levels.…”

Section: Discussionmentioning

confidence: 99%

Cell-Specific Protective Signaling Induced by the Novel AT2R-Agonist NP-6A4 on Human Endothelial and Smooth Muscle Cells

Toedebusch¹,

Belenchia²,

Pulakat³

2018

Front. Pharmacol.

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Cardiovascular disease incidence continues to rise and new treatment paradigms are warranted. We reported previously that activation of Angiotensin II receptor (encoded by the X-linked Agtr2 gene) by a new peptide agonist, NP-6A4, was more effective in protecting mouse cardiomyocyte HL-1 cells and human coronary artery vascular smooth muscle cells (hCAVSMCs) from acute nutrient deficiency than other drugs tested. To elucidate further the protective effects of NP-6A4 in human cells, we studied the effects of NP-6A4 treatment on functions of human coronary artery endothelial cells (hCAECs), and hCAVSMCs. In hCAVSMCs, NP-6A4 (1 μM) increased Agtr2 mRNA (sixfold, p < 0.05) after 12-h exposure, whereas in hCAECs, significant increase in Agtr2 mRNA (hCAECs: eightfold) was observed after prolonged exposure. Interestingly, NP-6A4 treatment (1 μM, 12 h) increased AT2R protein levels in all human cells tested. Pre-treatment with AT2R-antagonist PD123319 (20 μM) and anti-AT2R siRNA (1 μM) suppressed this effect. Thus, NP-6A4 activates a positive feedback loop for AT2R expression and signaling in hCAVSMCs and hCAECs. NP-6A4 (1–20 μM) increased cell index (CI) of hCAVSMCs as determined by real time cell analyzer (RTCA), indicating that high concentrations of NP-6A4 were not cytotoxic for hCAVSMCs, rather promoting better cell attachment and growth. Seahorse Extracellular Flux Assay revealed that NP-6A4 (1 μM) treatment for 7 days increased whole cell-based mitochondrial parameters of hCAVSMCs, specifically maximal respiration (p < 0.05), spare respiratory capacity (p < 0.05) and ATP production (p < 0.05). NP-6A4 (1 μM; 7 days) also suppressed Reactive Oxygen Species (ROS) in hCAVSMCs. Exposure to Doxorubicin (DOXO) (1 μM) increased ROS in hCAVSMCs and this effect was suppressed by NP-6A4 (1 μM). In hCAECs grown in complete medium, NP-6A4 (1 μM) and Ang II (1 μM) exerted similar changes in CI. Additionally, NP-6A4 (5 μM: 12 h) increased expression of eNOS (sixfold, p < 0.05) and generation of nitric oxide (1.3-fold, p < 0.05) in hCAECs and pre-treatment with PD123319 (20 μM) suppressed this effect partially (65%). Finally, NP-6A4 decreased phosphorylation of Jun-N-terminal kinase, implicated in apoptosis of ECs in atherosclerotic sites. Taken together, NP-6A4, through its ability to increase AT2R expression and signaling, exerts different cell-specific protective effects in human VSMCs and ECs.

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Section: Discussionmentioning

confidence: 99%

Cell-Specific Protective Signaling Induced by the Novel AT2R-Agonist NP-6A4 on Human Endothelial and Smooth Muscle Cells

Toedebusch¹,

Belenchia²,

Pulakat³

2018

Front. Pharmacol.

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“…Ang II stimulates apoptosis in intestinal epithelial cells via the AT 2 receptor61. Activation of AT 2 by CGP-42112a causes increased nitric oxide production in jejunal mucosa62. Low-dose Ang II delivery stimulates jejunal water and electrolyte absorption, and this effect appears to be mediated through an AT 2 -cGMP signaling mechanism63.…”

Section: Discussionmentioning

confidence: 99%

Dietary Sodium Suppresses Digestive Efficiency via the Renin-Angiotensin System

Weidemann

Voong

Morales-Santiago

et al. 2015

Sci Rep

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Dietary fats and sodium are both palatable and are hypothesized to synergistically contribute to ingestive behavior and thereby obesity. Contrary to this hypothesis, C57BL/6J mice fed a 45% high fat diet exhibited weight gain that was inhibited by increased dietary sodium content. This suppressive effect of dietary sodium upon weight gain was mediated specifically through a reduction in digestive efficiency, with no effects on food intake behavior, physical activity, or resting metabolism. Replacement of circulating angiotensin II levels reversed the effects of high dietary sodium to suppress digestive efficiency. While the AT1 receptor antagonist losartan had no effect in mice fed low sodium, the AT2 receptor antagonist PD-123,319 suppressed digestive efficiency. Correspondingly, genetic deletion of the AT2 receptor in FVB/NCrl mice resulted in suppressed digestive efficiency even on a standard chow diet. Together these data underscore the importance of digestive efficiency in the pathogenesis of obesity, and implicate dietary sodium, the renin-angiotensin system, and the AT2 receptor in the control of digestive efficiency regardless of mouse strain or macronutrient composition of the diet. These findings highlight the need for greater understanding of nutrient absorption control physiology, and prompt more uniform assessment of digestive efficiency in animal studies of energy balance.

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“…As of January 2014, Ͼ37,000 bacterial genome sequencing projects have been completed or are ongoing (http://www.genomesonline.org/). These sequences are then made available in public databases, facilitating whole-genome sequence comparisons of new bacterial strains (264,265). In 1999, Fitz-Gibbon and House were the first to propose that the presence or absence of genes within genomes could be used to describe taxonomic relations among prokaryotes (266).…”

Section: From Culturomics To Taxonogenomicsmentioning

confidence: 99%

The Rebirth of Culture in Microbiology through the Example of Culturomics To Study Human Gut Microbiota

et al. 2015

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SUMMARY Bacterial culture was the first method used to describe the human microbiota, but this method is considered outdated by many researchers. Metagenomics studies have since been applied to clinical microbiology; however, a “dark matter” of prokaryotes, which corresponds to a hole in our knowledge and includes minority bacterial populations, is not elucidated by these studies. By replicating the natural environment, environmental microbiologists were the first to reduce the “great plate count anomaly,” which corresponds to the difference between microscopic and culture counts. The revolution in bacterial identification also allowed rapid progress. 16S rRNA bacterial identification allowed the accurate identification of new species. Mass spectrometry allowed the high-throughput identification of rare species and the detection of new species. By using these methods and by increasing the number of culture conditions, culturomics allowed the extension of the known human gut repertoire to levels equivalent to those of pyrosequencing. Finally, taxonogenomics strategies became an emerging method for describing new species, associating the genome sequence of the bacteria systematically. We provide a comprehensive review on these topics, demonstrating that both empirical and hypothesis-driven approaches will enable a rapid increase in the identification of the human prokaryote repertoire.

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The angiotensin II receptor type 2 agonist CGP 42112A stimulates NO production in the porcine jejunal mucosa

Cited by 21 publications

References 28 publications

Cell-Specific Protective Signaling Induced by the Novel AT2R-Agonist NP-6A4 on Human Endothelial and Smooth Muscle Cells

Cell-Specific Protective Signaling Induced by the Novel AT2R-Agonist NP-6A4 on Human Endothelial and Smooth Muscle Cells

Dietary Sodium Suppresses Digestive Efficiency via the Renin-Angiotensin System

The Rebirth of Culture in Microbiology through the Example of Culturomics To Study Human Gut Microbiota

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