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Inhibitory effect of caffeic acid on ADP-induced thrombus formation and platelet activation involves mitogen-activated protein kinases.

Lu Y, Li Q, Liu YY, Sun K, Fan JY, Wang CS, Han JY - Sci Rep (2015)

Bottom Line: In this study, we investigated the antithrombotic effect of CA in mouse cerebral arterioles and venules using intravital microscopy.Our results demonstrated that CA (1.25-5 mg/kg) significantly inhibited thrombus formation in vivo.Additionally, CA attenuated p38, ERK, and JNK activation, and enhanced cAMP levels.

View Article: PubMed Central - PubMed

Affiliation: Department of gynaecology, Beijing Royal Integrative Medicine Hospital, Beijing, China.

ABSTRACT
Caffeic acid (CA), one of the active constituents of Radix Salvia miltiorrhizae, exhibits antioxidant and anti-inflammatory activities. However, few studies have assessed the ability of CA to inhibit platelet mediated thrombus generation in vivo. In this study, we investigated the antithrombotic effect of CA in mouse cerebral arterioles and venules using intravital microscopy. The antiplatelet activity of CA in ADP stimulated mouse platelets in vitro was also examined in attempt to explore the underlying mechanism. Our results demonstrated that CA (1.25-5 mg/kg) significantly inhibited thrombus formation in vivo. In vitro, CA (25-100 μM) inhibited ADP-induced platelet aggregation, P-selectin expression, ATP release, Ca(2+) mobilization, and integrin αIIbβ3 activation. Additionally, CA attenuated p38, ERK, and JNK activation, and enhanced cAMP levels. Taken together, these data provide evidence for the inhibition of CA on platelet-mediated thrombosis in vivo, which is, at least partly, mediated by interference in phosphorylation of ERK, p38, and JNK leading to elevation of cAMP and down-regulation of P-selectin expression and αIIbβ3 activation. These results suggest that CA may have potential for the treatment of aberrant platelet activation-related diseases.

No MeSH data available.


Related in: MedlinePlus

Effects of CA on photochemically induced arterial thrombosis.(A) Representative images of thrombus formation in mouse cerebral arterioles induced by photochemical injury in different conditions and at different time points. In order to compare the activities of CA and clopidogrel at a similar blood concentration, 5 mg/kg of CA (MW: 180.16) and 12 mg/kg of clopidogrel (MW: 419.90) were continuously infused through the catheterized femoral vein starting from 20 min prior to the vessel wall injury. This resulted in approximately the same blood concentration of CA and clopidogrel in mice in vivo. Arrows indicate irreversible arteriolar vessel occlusion. (B) Dot plots of arteriolar occlusion time from five to six experiments. #p < 0.05 vs Model group.
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f2: Effects of CA on photochemically induced arterial thrombosis.(A) Representative images of thrombus formation in mouse cerebral arterioles induced by photochemical injury in different conditions and at different time points. In order to compare the activities of CA and clopidogrel at a similar blood concentration, 5 mg/kg of CA (MW: 180.16) and 12 mg/kg of clopidogrel (MW: 419.90) were continuously infused through the catheterized femoral vein starting from 20 min prior to the vessel wall injury. This resulted in approximately the same blood concentration of CA and clopidogrel in mice in vivo. Arrows indicate irreversible arteriolar vessel occlusion. (B) Dot plots of arteriolar occlusion time from five to six experiments. #p < 0.05 vs Model group.

Mentions: We first tested the effects of CA on arteriole thrombus formation in vivo using intravital microscopy in a mouse cerebral thrombosis model induced by photochemical injury. As shown in Fig. 2A, before photochemical injury, few, if any, fluorescently labeled platelets (bright dots) transiently adhered on the vessel wall. The photochemical injury rapidly provoked platelet adhesion on the arteriolar wall thus building-up of platelet thrombus. The vessel occlusion was often seen in the arterioles within 3 min after injury (Fig. 2B). Pretreatment with CA at 1.25 and 5 mg/kg both significantly decreased platelet deposition and prolonged the time required for thrombus formation and vessel occlusion with 5 mg/kg being more efficient reaching an effect equivalent to clopidogrel (12 mg/kg) (Fig. 2A,B). Treatment with CA at 0.25 mg/kg had no significant effect on the time required for vessel occlusion, though platelet deposition and thrombus formation were attenuated in this case (Fig. 2A,B).


Inhibitory effect of caffeic acid on ADP-induced thrombus formation and platelet activation involves mitogen-activated protein kinases.

Lu Y, Li Q, Liu YY, Sun K, Fan JY, Wang CS, Han JY - Sci Rep (2015)

Effects of CA on photochemically induced arterial thrombosis.(A) Representative images of thrombus formation in mouse cerebral arterioles induced by photochemical injury in different conditions and at different time points. In order to compare the activities of CA and clopidogrel at a similar blood concentration, 5 mg/kg of CA (MW: 180.16) and 12 mg/kg of clopidogrel (MW: 419.90) were continuously infused through the catheterized femoral vein starting from 20 min prior to the vessel wall injury. This resulted in approximately the same blood concentration of CA and clopidogrel in mice in vivo. Arrows indicate irreversible arteriolar vessel occlusion. (B) Dot plots of arteriolar occlusion time from five to six experiments. #p < 0.05 vs Model group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4561902&req=5

f2: Effects of CA on photochemically induced arterial thrombosis.(A) Representative images of thrombus formation in mouse cerebral arterioles induced by photochemical injury in different conditions and at different time points. In order to compare the activities of CA and clopidogrel at a similar blood concentration, 5 mg/kg of CA (MW: 180.16) and 12 mg/kg of clopidogrel (MW: 419.90) were continuously infused through the catheterized femoral vein starting from 20 min prior to the vessel wall injury. This resulted in approximately the same blood concentration of CA and clopidogrel in mice in vivo. Arrows indicate irreversible arteriolar vessel occlusion. (B) Dot plots of arteriolar occlusion time from five to six experiments. #p < 0.05 vs Model group.
Mentions: We first tested the effects of CA on arteriole thrombus formation in vivo using intravital microscopy in a mouse cerebral thrombosis model induced by photochemical injury. As shown in Fig. 2A, before photochemical injury, few, if any, fluorescently labeled platelets (bright dots) transiently adhered on the vessel wall. The photochemical injury rapidly provoked platelet adhesion on the arteriolar wall thus building-up of platelet thrombus. The vessel occlusion was often seen in the arterioles within 3 min after injury (Fig. 2B). Pretreatment with CA at 1.25 and 5 mg/kg both significantly decreased platelet deposition and prolonged the time required for thrombus formation and vessel occlusion with 5 mg/kg being more efficient reaching an effect equivalent to clopidogrel (12 mg/kg) (Fig. 2A,B). Treatment with CA at 0.25 mg/kg had no significant effect on the time required for vessel occlusion, though platelet deposition and thrombus formation were attenuated in this case (Fig. 2A,B).

Bottom Line: In this study, we investigated the antithrombotic effect of CA in mouse cerebral arterioles and venules using intravital microscopy.Our results demonstrated that CA (1.25-5 mg/kg) significantly inhibited thrombus formation in vivo.Additionally, CA attenuated p38, ERK, and JNK activation, and enhanced cAMP levels.

View Article: PubMed Central - PubMed

Affiliation: Department of gynaecology, Beijing Royal Integrative Medicine Hospital, Beijing, China.

ABSTRACT
Caffeic acid (CA), one of the active constituents of Radix Salvia miltiorrhizae, exhibits antioxidant and anti-inflammatory activities. However, few studies have assessed the ability of CA to inhibit platelet mediated thrombus generation in vivo. In this study, we investigated the antithrombotic effect of CA in mouse cerebral arterioles and venules using intravital microscopy. The antiplatelet activity of CA in ADP stimulated mouse platelets in vitro was also examined in attempt to explore the underlying mechanism. Our results demonstrated that CA (1.25-5 mg/kg) significantly inhibited thrombus formation in vivo. In vitro, CA (25-100 μM) inhibited ADP-induced platelet aggregation, P-selectin expression, ATP release, Ca(2+) mobilization, and integrin αIIbβ3 activation. Additionally, CA attenuated p38, ERK, and JNK activation, and enhanced cAMP levels. Taken together, these data provide evidence for the inhibition of CA on platelet-mediated thrombosis in vivo, which is, at least partly, mediated by interference in phosphorylation of ERK, p38, and JNK leading to elevation of cAMP and down-regulation of P-selectin expression and αIIbβ3 activation. These results suggest that CA may have potential for the treatment of aberrant platelet activation-related diseases.

No MeSH data available.


Related in: MedlinePlus