Friday, November 22, 2024
11/22/2024
Venous thromboembolism (VTE), which comprises deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third most common cause of vascular death after a heart attack and stroke. VTE is responsible for 300 000 deaths annually in the USA alone. Although the development of direct oral anticoagulants has improved the treatment of VTE, there are still significant bleeding risks associated with anticoagulant therapy. A better understanding of the pathogenesis of VTE would aid in developing novel, effective and safer drugs. Although the etiologic factors of DVT codified by Virchow’s triad, i.e., hypercoagulability, blood stasis, and endothelial cell dysfunction, are still relevant, recent studies suggest that DVT is primarily a thromboinflammatory-mediated event. This opens a new possibility that suppression of thromboinflammation may be an ideal approach to prevent and treat VTE. The endothelium is an important contributor to thromboinflammation in DVT. Our recent studies show that Gab2 (Grb2-associated binder2), a signaling adapter protein, plays a central and key role in integrating inflammatory signaling initiated by diverse inflammatory stimuli in endothelial cells. Our studies identify for the first time that Gab2 mediates the assembly of the CBM (CARMA3-BCL10-MALT1) signalosome in endothelial cells in response to inflammatory stimuli. Gab2-mediated CBM signalosome not only leads to the activation of NF-kB and prothrombotic gene expression but also exocytosis of P-selectin and VWF via activation of the Rho signaling pathway. In vivo studies show that global deficiency of Gab2 or inhibition of MALT1 in the CBM signalosome by specific pharmacological inhibitors protects against LPS- and S. pneumoniae infection- induced inflammation and inferior vena cava (IVC) ligation-induced venous thrombosis. These studies identify novel inflammatory signaling mechanisms and suggest they could play a crucial role in venous thrombosis. However, many knowledge gaps exist still in our understanding of these mechanisms and their contribution to VTE. We hypothesize that endothelial Gab2-MALT1-mediated signaling plays a crucial role in thromboinflammation and contributes to the pathogenesis of VTE and targeting Gab2-MALT1 signaling by pharmacological inhibition of MALT1 will have therapeutic potential in preventing and treating VTE. The specific aims are to (1) elucidate molecular mechanisms by which Gab2 mediates thromboinflammatory signaling in endothelial cells, (2) determine the role of endothelial Gab2-MALT1 signaling in venous thrombosis using cell-specific Gab2 and MALT1 knockout mice, (3) assess the influence of the Gab2-MALT1 signaling on venous thrombus resolution and vein wall injury. The proposed studies will employ innovative experimental approaches and unique transgenic mice Impact: Our proposed studies will provide novel insights into thromboinflammatory signaling in endothelial cells and other relevant cell types. Elucidating the role of Gab2- MALT1-mediated signaling in thromboinflammation and venous thrombosis would aid in developing novel and ideal therapeutic drugs to prevent and treat VTE without increasing bleeding risk.
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