Pekarova, Michaela, Koudelka, Adolf ORCID: 0000-0002-9998-8383, Kolarova, Hana, Ambrozova, Gabriela ORCID: 0000-0002-8172-9746, Klinke, Anna, Cerna, Anna, Kadlec, Jaroslav, Trundova, Maria, Svihalkova, Lenka Sindlerova, Kuchta, Radek, Kuchtova, Zdenka, Lojek, Antonin and Kubala, Lukas ORCID: 0000-0002-7729-7338 (2015). 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. Vasc. Pharmacol., 73. S. 138 - 149. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1879-3649

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Abstract

Pulmonary hypertension (PH), associated with imbalance in vasoactive mediators and massive remodeling of pulmonary vasculature, represents a serious health complication. Despite the progress in treatment, PH patients typically have poor prognoses with severely affected quality of life. Asymmetric dimethyl arginine (ADMA), endogenous inhibitor of endothelial nitric oxide synthase (eNOS), also represents one of the critical regulators of pulmonary vascular functions. The present study describes a novel mechanism of ADMA-induced dysfunction in human pulmonary endothelial and smooth muscle cells. The effect of ADMA was compared with well-established model of hypoxia-induced pulmonary vascular dysfunction. It was discovered for the first time that ADMA induced the activation of signal transducer and activator of transcription 3 (STAT3) and stabilization of hypoxia inducible factor la (HIF-1 alpha) in both types of cells, associated with drastic alternations in normal cellular functions (e.g., nitric oxide production, cell proliferation/Ca2+ concentration, production of pro-inflammatory mediators, and expression of eNOS, DDAH1, and ICAM-1). Additionally, ADMA significantly enhanced the hypoxia-mediated increase in the signaling cascades. In summary, increased ADMA may lead to manifestation of PH phenotype in human endothelial and smooth muscle cells via the STAT3/HIF-1 alpha cascade. Therefore this signaling pathway represents the potential pathway for future clinical interventions in PH. (C) 2015 Elsevier Inc. All rights reserved.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Pekarova, MichaelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koudelka, AdolfUNSPECIFIEDorcid.org/0000-0002-9998-8383UNSPECIFIED
Kolarova, HanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ambrozova, GabrielaUNSPECIFIEDorcid.org/0000-0002-8172-9746UNSPECIFIED
Klinke, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cerna, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kadlec, JaroslavUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trundova, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Svihalkova, Lenka SindlerovaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuchta, RadekUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuchtova, ZdenkaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lojek, AntoninUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kubala, LukasUNSPECIFIEDorcid.org/0000-0002-7729-7338UNSPECIFIED
URN: urn:nbn:de:hbz:38-391609
DOI: 10.1016/j.vph.2015.06.005
Journal or Publication Title: Vasc. Pharmacol.
Volume: 73
Page Range: S. 138 - 149
Date: 2015
Publisher: ELSEVIER SCIENCE INC
Place of Publication: NEW YORK
ISSN: 1879-3649
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
NITRIC-OXIDE PRODUCTION; SMOOTH-MUSCLE-CELLS; ARTERIAL-HYPERTENSION; SYSTEMIC-SCLEROSIS; OXIDATIVE STRESS; FACTOR-I; STAT3; SUPEROXIDE; EXPRESSION; DISEASEMultiple languages
Pharmacology & PharmacyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/39160

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