The NF-κB specific inhibitor DHMEQ prevents thrombus formation in a mouse model of antiphospholipid syndrome

• Published in: Journal of nephropathology Vol. 2; no. 2; pp. 114 - 121
• Main Authors: Nishimura, Misato, Nii, Tokiko, Trimova, Gulzhan, Miura, Shuhei, Umezawa, Kazuo, Ushiyama, Akira, Kubota, Tetsuo
• Format: Journal Article
• Language: English
• Published: Society of Diabetic Nephropathy Prevention 01-04-2013
• Subjects: antiphospholipid syndrome; nf-kappa b; Original; thrombosis; tissue factor
• ISSN: 2251-8363; 2251-8819
• DOI: 10.12860/JNP.2013.19

Background:
β2-glycoprotein I (β2GPI)-dependent antiphospholipid antibodies (aPLs) are considered to play a pivotal pathogenic role in antiphospholipid syndrome (APS) by inducing the expression of tissue factor, inflammatory cytokines, and chemokines, most of which are dependent upon the NF-κB pathway. Therefore, the NF-κB is regarded as a promising target for the development of a novel therapeutic strategy. However, progress has been limited owing to the fact that there are no widely-used in vivo models, or highly specific inhibitors.
Objective:
This study aimed to test the effects of an NF-κB-specific inhibitor, DHMEQ, in preventing thrombus formation using an original mouse model of APS.
Materials and Methods:
Specificity of a monoclonal aPL WB-6 was examined by ELISA. WB-6 was injected into normal BALB/c mice with or without DHMEQ treatment. A pulse laser was radiated to a cutaneous vein in the window of a dorsal skinfold chamber attached to the mouse and thrombus formation was observed and recorded under a microscope.
Results:
WB-6 bound preferentially to the caldiolipin (CL)-β2GPI complex rather than to CL alone, or β2GPI alone. WB-6, but not isotype-matched control antibody, induced a prothrombotic state in the mice by inducing tissue factor expression upon circulating monocytes, resulting in thrombus formation at the site of laser-induced endothelial injury. This diathesis was almost completely ameliorated by DHMEQ treatment.
Conclusions:
Inhibition of the NF-κB pathway is a promising strategy for the development of a novel treatment for APS.