Abstract
The role of cannabinoids in thrombosis remains controversial. In view of the primary importance of tissue factor (TF) in blood coagulation and its involvement in the pathology of several cardiovascular, inflammatory and neoplastic diseases, a regulation of this initial procoagulant signal seems to be of particular interest. Using human umbilical vein endothelial cells (HUVEC) the present study investigated the impact of the synthetic cannabinoid WIN 55,212-2 on interleukin (IL)-1β-induced TF expression and activity. WIN 55,212-2 caused a time- and concentration-dependent suppression of IL-1β-induced TF protein accompanied by decreases in TF mRNA and activity. Inhibition of TF protein expression by WIN 55,212-2 was mimicked by its cannabinoid receptor-inactive enantiomer WIN 55,212-3 but not by structurally unrelated phyto-, endo- and synthetic cannabinoids. In addition, the inhibitory effect of WIN 55,212-2 was not reversed by antagonists to cannabinoid receptors (CB1, CB2) or transient receptor potential vanilloid 1. Mechanistic approaches revealed WIN 55,212-2 to suppress IL-1β-induced TF expression via inhibition of ceramide formation and via decreased phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinases. Further inhibitor experiments demonstrated neutral sphingomyelinase (nSMase) to confer ceramide generation upon IL-1β treatment with the parallel IL-1β-mediated activation of MAPKs occurring via an nSMase-independent pathway. Finally, a receptor-independent inhibition of IL-1β-induced TF protein by WIN 55,212-2 was confirmed in human blood monocytes. Collectively, this data provide a hitherto unknown receptor-independent anticoagulatory action of the cannabinoid WIN 55,212-2.
Highlights
Tissue factor (TF), formerly known as thromboplastin, is a critical initiator of physiologic and pathophysiologic coagulation
Treatment of human umbilical vein endothelial cells (HUVEC) with the synthetic cannabinoid WIN 55,212-2 at 10 μM concomitantly to IL-1β was associated with a significant suppression of IL-1β-induced TF protein (Figure 1A) and mRNA levels (Figure 1B) within an 8-h incubation period
The mechanism elicited by WIN 55,212-2 was shown to include an interference with IL-1β-induced ceramide formation and activation of p38 mitogen-activated protein kinase (MAPK) and Jun N-terminal kinases (JNK) (Figure 9)
Summary
Tissue factor (TF), formerly known as thromboplastin, is a critical initiator of physiologic and pathophysiologic coagulation. TF is constitutively expressed in vascular smooth muscle cells leading to its rapid exposure to circulating blood following disruption of the endothelial layer [3]. In endothelial cells and monocytes TF is expressed to a limited extent only, but becomes upregulated by diverse stimuli, such as lipopolysaccharide, proinflammatory cytokines (e.g. tumor necrosis factor (TNF) and interleukin (IL)-1β), growth factors, oxidized low density lipoprotein, hypoxia, shear stress and oxidants (for review see [1, 2]). A cytokine-driven increased TF expression on the monocyte surface facilitates the interaction of the monocyte with activated platelets and endothelial cells via binding of P-selectin, resulting in fibrin deposition and thrombus formation (for review see [10, 11])
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