Intracellular signaling triggered by antiphospholipid antibodies in platelets and endothelial cells: a pathway to targeted therapies.
Understanding the intracellular events triggered by antiphospholipid (aPL) antibodies in platelets and endothelial cells (ECs) is important in designing new modalities of targeted therapies for the treatment of thrombosis in Antiphospholipid Syndrome (APS). A recent study showed a significant increase in the expression of GPIIb/IIIa on platelets treated with aPL antibodies and a thrombin receptor peptide agonist (TRAP), and these effects were abrogated by hydroxychloroquine (HQ). Hydroxychloroquine has also been shown to reduce in vivo aPL-induced thrombus formation. Furthermore, aPL-enhanced thrombosis in vivo can be abrogated by infusions of a GPIIb/IIIa antagonist (1B5) monoclonal antibody, and aPL-mediated thrombophilia is not observed in GPIIb/IIIa-deficient mice. Treatment of platelets with aPL antibodies has resulted in a significant increase in p38 mitogen-activated protein kinase (p38MAPK) phosphorylation and aPL-induced platelet aggregation and thromboxane B2 (TXB2) production was abrogated by SB203580 (a p38MAPK inhibitor). aPL antibodies induce increased expression, function and transcription of tissue factor (TF) on EC. Activation of ECs and thrombogenicity of aPL in vivo can be reversed by treatment of the animals with statins. Upregulation of TF on ECs can also be abrogated by treatment of the cells with fluvastatin. There is also indication of activation of nuclear factor kappa B (NFkappaB), increase in phosphorylation of p38MAPK in ECs by aPL antibodies that can be reversed by specific inhibitors MG132 and SB203580, respectively. The data open the possibility to new treatment modalities that may include the use of hydroxychloroquine, statins, specific antagonists of GPIIb/IIIa (such as abciximab or equivalent) and specific p38MAPK inhibitors, after the completion of well-designed clinical studies.
Pierangeli
Silvia S
SS
Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA 30310-1495, USA. pierans@msm.edu
Vega-Ostertag
Mariano
M
Harris
E Nigel
EN
D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000737:chemistry; D016736:Antiphospholipid Syndrome / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006886:Hydroxychloroquine / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D015539:Platelet Activation; D018179:Receptors, Thrombin / Q000737:chemistry; D015398:Signal Transduction; D013927:Thrombosis / Q000473:pathology; D015854:Up-Regulation
D017152:Antibodies, Antiphospholipid; D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D018179:Receptors, Thrombin; D006886:Hydroxychloroquine