Abstract
Esculetin, a bioactive 6,7-dihydroxy derivative of coumarin, possesses pharmacological activities against obesity, diabetes, renal failure, and cardiovascular disorders (CVDs). Platelet activation plays a major role in CVDs. Thus, disrupting platelet activation represents an attractive therapeutic target. We examined the effect of esculetin in human platelet activation and experimental mouse models. At 10–80 μM, esculetin inhibited collagen- and arachidonic acid-induced platelet aggregation in washed human platelets. However, it had no effects on other agonists such as thrombin and U46619. Esculetin inhibited adenosine triphosphate release, P-selectin expression, hydroxyl radical (OH·) formation, Akt activation, and phospholipase C (PLC)γ2/protein kinase C (PKC) phosphorylation, but did not diminish mitogen-activated protein kinase phosphorylation in collagen-activated human platelets. Platelet function analysis indicated that esculetin substantially prolonged the closure time of whole blood. In experimental mice, esculetin significantly increased the occlusion time in thrombotic platelet plug formation and reduced mortality associated with acute pulmonary thromboembolism. However, it did not prolong the bleeding time. This study demonstrates that esculetin inhibits human platelet activation via hindering the PLCγ2–PKC cascade, hydroxyl radical formation, Akt activation, and ultimately suppressing platelet activation. Therefore, esculetin may act as an essential therapeutic agent for preventing thromboembolic diseases.
Highlights
Arterial thrombosis is involved in a wide variety of coronary heart diseases, cerebrovascular diseases, and rheumatic heart diseases as well as in myocardial infarction and other conditions
Esculetin (10–80 μM) (Figure 1A) exhibited strong effectiveness for inhibiting platelet aggregation stimulated by arachidonic acid (AA; 60 μM) and collagen (1 μg/mL), but not by thrombin (0.01 U/mL) or 1 μM 9,11-dideoxy-11α,9α-epoxymethanoprostaglandin (U46619), a prostaglandin endoperoxide (Figure 1B,C)
Both AA- and collagen-induced platelet aggregation was completely inhibited by esculetin at 80 μM concentration
Summary
Arterial thrombosis is involved in a wide variety of coronary heart diseases, cerebrovascular diseases, and rheumatic heart diseases as well as in myocardial infarction and other conditions. Cyclooxygenase inhibitors [2], adenosine diphosphate (ADP) receptor antagonists [3], and glycoprotein (GP) IIb/IIIa receptor antagonists [4] are the most commonly prescribed antiplatelet agents Responses to these drugs vary, and their use is associated with a risk of bleeding. Collagen receptors glycoprotein VI (GPVI) and integrin α2β1 induce phospholipase Cγ2 (PLCγ2) and protein kinase C (PKC) activation, facilitate platelet granule release [5], and subsequently stimulate platelet aggregation. These routes are essential for platelet activation and thrombus formation. Since GPVI is an encouraging pharmacological target for the active and safe treatment of thrombotic diseases [6], inhibition of PLCγ2, PKC, and adenosine triphosphate (ATP) release are the major targets for the treatment of thrombotic diseases
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