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


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.
Tokyo Medical and Dental University Graduate School of Health Care Sciences, Tokyo, Japan.
Misato
M
Nishimura
Tokyo Medical and Dental University Graduate School of Health Care Sciences, Tokyo, Japan.
Tokiko
T
Nii
Tokyo Medical and Dental University Graduate School of Health Care Sciences, Tokyo, Japan.
Gulzhan
G
Trimova
Tokyo Medical and Dental University Graduate School of Health Care Sciences, Tokyo, Japan.
Shuhei
S
Miura
Department of Molecular Target Medicine Screening, Aichi Medical University School of Medicine, Aichi, Japan.
Kazuo
K
Umezawa
Department of Environmental Health, National Institute of Public Health, Saitama, Japan.
Akira
A
Ushiyama
Tokyo Medical and Dental University Graduate School of Health Care Sciences, Tokyo, Japan.
Tetsuo
T
Kubota
Antiphospholipid syndrome; NF-kappa B; Thrombosis; Tissue factor