Background: Atherosclerosis is characterized by endothelial dysfunction, increased expression of cellular adhesion molecules, and accumulation of oxidized low-density lipoprotein (oxLDL). While it has been shown that oxLDL signals through the Src and TEC-family kinase pathway to potentiate platelet activation in vitro, whether TEC-family kinases regulate platelet and endothelial cell (EC) activity during the development and progression of atherosclerosis in vivo is unclear.

Aims: Investigate the role of the TEC-family kinase pathway in oxLDL-mediated platelet activity in vitro, and platelet and EC dysfunction in vivo.

Methods: Platelet aggregation in response to platelet agonist, oxLDL, was measured using light aggregometry. Platelet integrin activation and granule secretion in response to glycoprotein VI-agonist, cross-linked collagen-related peptide (CRP-XL), were measured using flow cytometry. In a nonhuman primate model (NHP) of early atherosclerosis, two obese rhesus macaques were administered the TEC-family kinase inhibitor, ibrutinib, for one week. Targeted contrast-enhanced ultrasound molecular imaging was used to measure vascular cell adhesion molecule-1 (VCAM-1) as a marker of EC activity and platelet glycoprotein-Ibα (GPIbα) at the carotid bifurcation before and after treatment with a TEC-family kinase inhibitor. 

Results: Platelet aggregation in response to oxLDL was inhibited following pre-incubation with two pharmacologically distinct TEC-family kinase inhibitors, including the Bruton’s tyrosine kinase inhibitor, ibrutinib. We observed a reduction in platelet integrin activation and granule secretion in response to CRP-XL following pre-incubation with ibrutinib. In a NHP model of early atherosclerosis, in vivo molecular imaging showed that treatment with ibrutinib decreased signal for both EC VCAM-1 and platelet GPIbα. 

Conclusions: oxLDL potentiates platelet activity in vitro through TEC-family kinase pathway, while the TEC-family kinase inhibitor, ibrutinib, decreased the markers of EC dysfunction and platelet activity in vivo. These results suggest that TEC family kinases contribute to the pathogenesis of atherosclerosis and could represent a novel therapeutic target.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/the-role-of-tec-family-kinases-in-oxldl-mediated-platelet-activity-in-vitro-and-platelet-and-endothelial-dysfunction-in-vivo/