Hippo-YAP signaling: A novel pathway regulating platelet activation and thrombogenesis.

Aim

To investigate the functional significance of Hippo-YAP signaling in platelet activation and thrombosis.

Methods

Expression and phosphorylation of YAP were examined in platelets exposed to physiological agonists as well as mechanical cues (adhesion to matrices having varying stiffness and activation of mechanosensitive channel Piezo1). Involvements of LATS kinase and RhoA-ROCK-actomyosin axis in YAP signaling were evaluated. Effect of pharmacological inhibition of YAP on platelet activation parameters (αIIbβ3 activation, adhesion, α-granule secretion, extracellular vesicle release, and fibrin clot retraction) were studied ex vivo. Contribution of YAP to pathological thrombosis was further investigated in a murine model in vivo. YAP activity was also assessed in platelets obtained from patients diagnosed with acute coronary syndrome. KEY

Findings

Platelets expressed mRNA transcript as well as peptide of YAP, whose phosphorylation (at Ser-127) was modulated in response to physiological agonists and mechanical stimuli. Adhesion to immobilized matrix, Piezo1 stimulation, and exposure to agonists markedly enhanced YAP expression. Concomitantly, these factors prompted dephosphorylation of YAP, suggestive of YAP functional impairment, driven by the upstream LATS kinase and RhoA-ROCK-actomyosin signaling axis. Inhibition of YAP impaired key platelet functions ex vivo, that included integrin αIIbβ3 activation, adhesion, α-granule secretion, extracellular vesicle release, and fibrin clot retraction, and exerted marked protection against pathological thrombosis in a murine model in vivo. Consistent with above, platelets obtained from patients diagnosed with acute coronary syndrome were found to harbour enhanced YAP activity.

Conclusion

These findings underscore a contributing role of YAP in thrombogenesis, highlighting its potential as an antiplatelet therapeutic target.