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Int. J. Mol. Sci. 2019, 20(1), 105; https://doi.org/10.3390/ijms20010105

NFκB Inhibition Mitigates Serum Amyloid A-Induced Pro-Atherogenic Responses in Endothelial Cells and Leukocyte Adhesion and Adverse Changes to Endothelium Function in Isolated Aorta

1
Discipline of Pathology, Sydney Medical School, The University of Sydney, Camperdown, NSW 2006, Australia
2
Heart Research Institute, Newton, NSW 2053, Australia
3
Baker Heart and Diabetes Institute, Victoria 3004, Australia
4
Department of Medicine, Monash University, Victoria 3500, Australia
5
Cardiovascular Disease Program, Biomedicine Discovery Institute, Monash University £Department of Pharmacology, Monash University, Victoria 3800, Australia
6
Department of Immunology, Monash University, Victoria 3004, Australia
7
Department of Physiology, Anatomy & Microbiology, School of Life Sciences, La Trobe University, Bundoora, VIC 3083, Australia
*
Author to whom correspondence should be addressed.
Received: 31 October 2018 / Revised: 14 December 2018 / Accepted: 18 December 2018 / Published: 28 December 2018
(This article belongs to the Special Issue Vascular Endothelial Cells)
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PDF [4387 KB, uploaded 28 December 2018]
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Abstract

The acute phase protein serum amyloid A (SAA) is associated with endothelial dysfunction and early-stage atherogenesis. Stimulation of vascular cells with SAA increases gene expression of pro-inflammation cytokines and tissue factor (TF). Activation of the transcription factor, nuclear factor kappa-B (NFκB), may be central to SAA-mediated endothelial cell inflammation, dysfunction and pro-thrombotic responses, while targeting NFκB with a pharmacologic inhibitor, BAY11-7082, may mitigate SAA activity. Human carotid artery endothelial cells (HCtAEC) were pre-incubated (1.5 h) with 10 μM BAY11-7082 or vehicle (control) followed by SAA (10 μg/mL; 4.5 h). Under these conditions gene expression for TF and Tumor Necrosis Factor (TNF) increased in SAA-treated HCtAEC and pre-treatment with BAY11-7082 significantly (TNF) and marginally (TF) reduced mRNA expression. Intracellular TNF and interleukin 6 (IL-6) protein also increased in HCtAEC supplemented with SAA and this expression was inhibited by BAY11-7082. Supplemented BAY11-7082 also significantly decreased SAA-mediated leukocyte adhesion to apolipoprotein E-deficient mouse aorta in ex vivo vascular flow studies. In vascular function studies, isolated aortic rings pre-treated with BAY11-7082 prior to incubation with SAA showed improved endothelium-dependent vasorelaxation and increased vascular cyclic guanosine monophosphate (cGMP) content. Together these data suggest that inhibition of NFκB activation may protect endothelial function by inhibiting the pro-inflammatory and pro-thrombotic activities of SAA. View Full-Text
Keywords: nuclear; transcription; endothelium; atherosclerosis; serum amyloid A; aorta nuclear; transcription; endothelium; atherosclerosis; serum amyloid A; aorta
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Vallejo, A.; Chami, B.; Dennis, J.M.; Simone, M.; Ahmad, G.; Abdo, A.I.; Sharma, A.; Shihata, W.A.; Martin, N.; Chin-Dusting, J.P.F.; De Haan, J.B.; Witting, P.K. NFκB Inhibition Mitigates Serum Amyloid A-Induced Pro-Atherogenic Responses in Endothelial Cells and Leukocyte Adhesion and Adverse Changes to Endothelium Function in Isolated Aorta. Int. J. Mol. Sci. 2019, 20, 105.

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