Abstract
Background and Purpose: The ingestion of flavonoids has been reported to
be associated with reduced cardiovascular disease risk. Among
flavonoids, quercitrin is the most common flavonoid in nature, and it
exhibits anti-oxidant properties. However, it is unclear whether
quercitrin plays a role in thrombogenesis. Experimental Approach: The
anti-platelet effect of quercitrin was assessed using platelet
aggregation, granule secretion, calcium mobilization, integrin
activation, and western blot. Antithrombotic effect was determined in
mouse using FeCl3-induced arterial thrombus formation in vivo and
thrombus formation on collagen-coated surfaces under arteriolar shear in
vitro. Transection tail bleeding time was used to evaluate adverse
effects. Key Results: Quercitrin significantly impaired CRP- or
U46619-induced platelet aggregation, granule secretion, ROS generation,
and intracellular Ca2+ mobilization. Outside-in signaling of αIIbβ3
integrin was significantly inhibited by quercitrin in a
concentration-dependent manner. The inhibitory effect of quercitrin
resulted from inhibition of the GPVI- or U46619-mediated phosphorylation
of PLC and PI3K signaling during platelet activation. Further, the
anti-oxidant effect is derived from decreased phosphorylation of
components of the TRAF4/p47phox/Hic5 axis signalosome. Oral
administration of quercitrin efficiently blocked FeCl3-induced arterial
thrombus formation in vivo and thrombus formation on collagen-coated
surfaces under arteriolar shear in vitro, without prolonging bleeding
time. Studies using a mouse model of ischemia/reperfusion-induced stroke
indicated that treatment with quercitrin reduced the infarct volume in
stroke. Conclusions and Implications: Our results demonstrated that
quercitrin could be an effective therapeutic agent for the treatment of
thrombotic diseases.