Asymmetric dimethyl arginine induces pulmonary vascular dysfunction via activation of signal transducer and activator of transcription 3 and stabilization of hypoxia-inducible factor 1-alpha

Pekarová, Michaela; Koudelka, Adolf; Kolářová, Hana; Ambrožová, Gabriela; Klinke, Anna; Cerna, Anna; Kadlec, Jaroslav; Trundová, Mária; Svihalkova, Lenka Sindlerova; Kuchta, Radek; Kuchtova, Zdenka; Lojek, Antonı́n; Kubala, Lukáš

doi:10.1016/j.vph.2015.06.005

Cited by 22 publications

(20 citation statements)

References 70 publications

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“…Cell viability was measured based on total cellular mass of adherent cells using the detergent-compatible protein assay reagent (Bio-Rad, USA) with bovine serum albumin as a standard [9]. Cell viability was not significantly decreased in any of the tested groups (data not shown).…”

Section: Methodsmentioning

confidence: 99%

“…The production of nitrites (the end product of NO metabolism in cultivation medium) was measured by the Griess assay [9]. Equal volume of supernatants (150 μl) and Griess reagent were mixed and incubated for 30 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

“…The expression of proteins was detected in cell lysates as described previously [9]. Briefly, an equal amount of proteins (25 μg) was loaded to 10 % SDS-polyacrylamide gel and transferred to immobilon polyvinylidene difluoride membrane (Immobilon-P, Millipore, Billerica, MA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…ADMA decreased the bioavailability of NO via inhibition of activation and expression of endothelial nitric oxide synthase (eNOS), responsible for NO synthesis in HPAEC [9]. Additionally, ADMA caused the up-regulation of pro-inflammatory mediator production (IL-6; ICAM-1; platelet-derived growth factor, PDGF; and Regulated on Activation Normal T cell Expressed and Secreted, RANTES) via STAT3/HIF-1 α signaling cascade, resulting in development of PH phenotype in HPAEC [9]. Based on the above-mentioned findings, we suggest that ADMA and STAT3/HIF-1 α cascade are potential therapeutic targets for future clinical interventions in PH.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, we decided to be the first to examine the effect of nitro-oleic acid (OA-NO 2 ), an exemplary NO 2 -FA, in our recently published hypoxia- and ADMA-induced model of endothelial dysfunction [9], which represents a highly suitable environment for testing the ability of different compounds to interfere with the development of the PH phenotype in human primary cells. Our experiments were focused on determination of specific molecules and proteins (NO, eNOS, IL-6, and ICAM-1), detection of adhesive properties and migration activity of HPAEC as well as on activation of specific signaling cascades (STAT3/HIF1a) involved in the development of PH [2, 17–19].…”

Section: Introductionmentioning

confidence: 99%

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Nitro-Oleic Acid Prevents Hypoxia- and Asymmetric Dimethylarginine-Induced Pulmonary Endothelial Dysfunction

Koudelka

Ambrožová

Klinke

et al. 2016

Cardiovasc Drugs Ther

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Rationale Pulmonary hypertension (PH) represents a serious health complication accompanied with hypoxic conditions, elevated levels of asymmetric dimethylarginine (ADMA), and overall dysfunction of pulmonary vascular endothelium. Since the prevention strategies for treatment of PH remain largely unknown, our study aimed to explore the effect of nitro-oleic acid (OA-NO2), an exemplary nitro-fatty acid (NO2-FA), in human pulmonary artery endothelial cells (HPAEC) under the influence of hypoxia or ADMA. Methods HPAEC were treated with OA-NO2 in the absence or presence of hypoxia and ADMA. The production of nitric oxide (NO) and interleukin-6 (IL-6) was monitored using the Griess method and ELISA, respectively. The expression or activation of different proteins (signal transducer and activator of transcription 3, STAT3; hypoxia inducible factor 1α, HIF-1α; endothelial nitric oxide synthase, eNOS; intercellular adhesion molecule-1, ICAM-1) was assessed by the Western blot technique. Results We discovered that OA-NO2 prevents development of endothelial dysfunction induced by either hypoxia or ADMA. OA-NO2 preserves normal cellular functions in HPAEC by increasing NO production and eNOS expression. Additionally, OA-NO2 inhibits IL-6 production as well as ICAM-1 expression, elevated by hypoxia and ADMA. Importantly, the effect of OA-NO2 is accompanied by prevention of STAT3 activation and HIF-1α stabilization. Conclusion In summary, OA-NO2 eliminates the manifestation of hypoxia- and ADMA-mediated endothelial dysfunction in HPAEC via the STAT3/HIF-1α cascade. Importantly, our study is bringing a new perspective on molecular mechanisms of NO2-FAs action in pulmonary endothelial dysfunction, which represents a causal link in progression of PH.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Nitro-Oleic Acid Prevents Hypoxia- and Asymmetric Dimethylarginine-Induced Pulmonary Endothelial Dysfunction

Koudelka

Ambrožová

Klinke

et al. 2016

Cardiovasc Drugs Ther

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Cyanobacterial harmful bloom lipopolysaccharides: pro-inflammatory effects on epithelial and immune cells in vitro

Skočková,

Raptová,

Pospíchalová

et al. 2023

Arch Toxicol

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Cyanobacterial harmful blooms (CyanoHABs) pose a global ecological problem, and their lipopolysaccharides (LPS) are among the bioactive compounds they release. Previous studies on CyanoHAB-LPS from single cyanobacterial species have shown varying bioactivities in different in vitro cell models. In this study, we isolated LPS from 19 CyanoHAB samples collected at 18 water bodies in the Czech Republic over two consecutive seasons. The proportions of cyanobacteria, Gram-negative bacteria (G-), and other bacteria in the biomass were determined by qPCR, while the cyanobacterial genera were identified using light microscopy. In vitro models of keratinocytes (HaCaT), the intestinal epithelium (co-culture of differentiated Caco-2 cells and peripheral blood mononuclear cells — PBMC), and PBMC alone were treated with isolated LPS at concentrations of 50, 100, and 1 µg/ml, respectively. The endotoxin activities of these concentrations were within the range measured in the aquatic environment. Approximately 85–90% of the samples displayed biological activity. However, the potency of individual LPS effects and response patterns varied across the different in vitro models. Furthermore, the observed activities did not exhibit a clear correlation with the taxonomic composition of the phytoplankton community, the relative share of microbial groups in the biomass, endotoxin activity of the LPS, or LPS migration and staining pattern in SDS-PAGE. These findings suggest that the effects of CyanoHAB-LPS depend on the specific composition and abundance of various LPS structures within the complex environmental sample and their interactions with cellular receptors.

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The miR-182/Myadm axis regulates hypoxia-induced pulmonary hypertension by balancing the BMP- and TGF-β-signalling pathways in an SMC/EC-crosstalk-associated manner

et al. 2021

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Asymmetric dimethyl arginine induces pulmonary vascular dysfunction via activation of signal transducer and activator of transcription 3 and stabilization of hypoxia-inducible factor 1-alpha

Cited by 22 publications

References 70 publications

Nitro-Oleic Acid Prevents Hypoxia- and Asymmetric Dimethylarginine-Induced Pulmonary Endothelial Dysfunction

Nitro-Oleic Acid Prevents Hypoxia- and Asymmetric Dimethylarginine-Induced Pulmonary Endothelial Dysfunction

Cyanobacterial harmful bloom lipopolysaccharides: pro-inflammatory effects on epithelial and immune cells in vitro

The miR-182/Myadm axis regulates hypoxia-induced pulmonary hypertension by balancing the BMP- and TGF-β-signalling pathways in an SMC/EC-crosstalk-associated manner

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