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.

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.

• Authors: Abigail Vallejo, Belal Chami, Joanne M Dennis, Martin Simone, Gulfam Ahmad, Adrian I Abdo, Arpeeta Sharma, Waled A Shihata, Nathan Martin, Jaye P F Chin-Dusting, Judy B de Haan, Paul K Witting
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 20 Issue 1 (Dec 28 2018) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 30597899 (Publication Type: Journal Article)

Chemical References

• Biomarkers
• Inflammation Mediators
• NF-kappa B
• Serum Amyloid A Protein

Topics

• Animals
• Aorta (metabolism, pathology)
• Atherosclerosis (etiology, metabolism)
• Biomarkers
• Cell Adhesion
• Endothelial Cells (metabolism)
• Endothelium, Vascular (metabolism)
• Gene Expression Regulation
• Humans
• Immunohistochemistry
• Inflammation Mediators
• Leukocytes (immunology, metabolism)
• NF-kappa B (metabolism)
• Rats
• Serum Amyloid A Protein (metabolism)