Atherothrombosis, the development of an occlusive clot in an artery, is triggered by atherosclerotic plaque rupture or erosion, and is the consequence of a complex interaction between multiple cell types in the blood and vasculature, with endothelial cells and platelets playing significant roles. The healthy endothelium prevents thrombosis whilst an activated or damaged endothelium favours thrombosis. Simultaneously targeting platelets and the endothelium could provide an effective anti-thrombotic therapeutic approach.
Pim kinases (Pim-1, -2, and -3), have been shown to modulate platelet function, and whilst shown to be expressed in endothelial cells, the role of Pim kinase in the thrombotic properties of the endothelium remains unknown.
The regulatory role for Pim kinase in endothelial cell control of thrombus formation in response to cigarette smoke extract (CSE) and TNFα, initiators of endothelial cell damage were therefore determined, using techniques including ELISA, immunofluorescence microscopy, qPCR, and Western Blotting.
We confirmed mRNA expression of all three Pim kinase isoforms, and protein expression of Pim-1 in human umbilical vein endothelial cells (HUVECs). HUVECs treated with CSE and TNFα demonstrated a decrease in eNOS levels, a protective mediator of cardiovascular homeostasis. To investigate whether Pim kinase plays a role, HUVECs were treated with AZD1208, a pan Pim kinase inhibitor, and a decrease in expression of VWF, a pro-coagulant mediator, and release of inflammatory markers, IL-6, and IL-8 were observed.
Collectively, these findings identify a potential role for Pim kinase in atherothrombosis and indicates that Pim kinase inhibitors could be repurposed for use alongside other anti-thrombotic agents for the prevention of cardiovascular-related events.
Conflict of Interest None
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