Efficacy of the Piperidine Nitroxide 4-MethoxyTEMPO in Ameliorating Serum Amyloid A-Mediated Vascular Inflammation
| Autor: | Abigail Vallejo, Belal Chami, Gulfam Ahmad, Nathan Martin, Albaraa A. Mojadadi, Paul K. Witting |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Mitochondrion Pharmacology chemistry.chemical_compound 0302 clinical medicine 4-MethoxyTEMPO Biomimetics Endothelial dysfunction Biology (General) Spectroscopy Aorta Cells Cultured chemistry.chemical_classification biology NF-kappa B General Medicine Intercellular Adhesion Molecule-1 Computer Science Applications Chemistry medicine.anatomical_structure Cardiovascular Diseases 030220 oncology & carcinogenesis nitroxide Nitrogen Oxides medicine.symptom Signal Transduction Endothelium endothelium QH301-705.5 Primary Cell Culture Vascular Cell Adhesion Molecule-1 Inflammation Nitric Oxide Catalysis Article Inorganic Chemistry Superoxide dismutase 03 medical and health sciences medicine Humans Serum amyloid A Physical and Theoretical Chemistry Molecular Biology Cyclic guanosine monophosphate QD1-999 Reactive oxygen species Serum Amyloid A Protein Superoxide Dismutase Organic Chemistry Endothelial Cells serum amyloid A medicine.disease 030104 developmental biology chemistry biology.protein Endothelium Vascular atherosclerosis Reactive Oxygen Species |
| Zdroj: | International Journal of Molecular Sciences International Journal of Molecular Sciences, Vol 22, Iss 4549, p 4549 (2021) Volume 22 Issue 9 |
| ISSN: | 1422-0067 |
| Popis: | Intracellular redox imbalance in endothelial cells (EC) can lead to endothelial dysfunction, which underpins cardiovascular diseases (CVD). The acute phase serum amyloid A (SAA) elicits inflammation through stimulating production of reactive oxygen species (ROS). The cyclic nitroxide 4-MethoxyTEMPO (4-MetT) is a superoxide dismutase mimetic that suppresses oxidant formation and inflammation. The aim of this study was to investigate whether 4-MetT inhibits SAA-mediated activation of cultured primary human aortic EC (HAEC). Co-incubating cells with 4-MetT inhibited SAA-mediated increases in adhesion molecules (VCAM-1, ICAM-1, E-selectin, and JAM-C). Pre-treatment of cells with 4-MetT mitigated SAA-mediated increases in transcriptionally activated NF-κB-p65 and P120 Catenin (a stabilizer of Cadherin expression). Mitochondrial respiration and ROS generation (mtROS) were adversely affected by SAA with decreased respiratory reserve capacity, elevated maximal respiration and proton leakage all characteristic of SAA-treated HAEC. This altered respiration manifested as a loss of mitochondrial membrane potential (confirmed by a decrease in TMRM fluorescence), and increased mtROS production as assessed with MitoSox Red. These SAA-linked impacts on mitochondria were mitigated by 4-MetT resulting in restoration of HAEC nitric oxide bioavailability as confirmed by assessing cyclic guanosine monophosphate (cGMP) levels. Thus, 4-MetT ameliorates SAA-mediated endothelial dysfunction through normalising EC redox homeostasis. Subject to further validation in in vivo settings these outcomes suggest its potential as a therapeutic in the setting of cardiovascular pathologies where elevated SAA and endothelial dysfunction is linked to enhanced CVD. |
| Databáze: | OpenAIRE |
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