Abstract
PURPOSE: Piperine, a major alkaloid of black pepper (Piper nigrum) and long pepper (Piper longum), was shown to have anti-inflammatory activity through the suppression of cyclooxygenase (COX)-2 gene expression and enzyme activity. It is also reported to exhibit anti-platelet activity, but the mechanism underlying this action remains unknown. In this study, we investigated a putative anti-platelet aggregation mechanism involving arachidonic acid (AA) metabolism and how this compares with the mechanism by which it inhibits macrophage inflammatory responses; METHODS: Rabbit platelets and murine macrophage RAW264.7 cells were treated with piperine, and the effect of piperine on the activity of AA-metabolizing enzymes, including cytosolic phospholipase A2 (cPLA2), COX-1, COX-2, and thromboxane A2 (TXA2) synthase, as well as its effect on AA liberation from the plasma membrane components, were assessed using isotopic labeling methods and enzyme immunoassay kit; RESULTS: Piperine significantly suppressed AA liberation by attenuating cPLA2 activity in collagen-stimulated platelets. It also significantly inhibited the activity of TXA2 synthase, but not of COX-1, in platelets. These results suggest that piperine inhibits platelet aggregation by attenuating cPLA2 and TXA2 synthase activities, rather than through the inhibition of COX-1 activity. On the other hand, piperine significantly inhibited lipopolysaccharide-induced generation of prostaglandin (PG)E2 and PGD2 in RAW264.7 cells by suppressing the activity of COX-2, without effect on cPLA2; CONCLUSION: Our findings indicate that piperine inhibits platelet aggregation and macrophage inflammatory response by different mechanisms.
Highlights
Platelet aggregation is a complex, rapidly progressing phenomenon that culminates in the formation of hemostatic plugs and arterial thrombi, which are recognized as potential sources of thromboembolic complications manifesting as atherosclerosis, heart attack, stroke, and peripheral vascular disease.Platelets are activated by various agonists, such as collagen and platelet-activating factor, and undergo a cascade of events that results in the enzymatic metabolism of arachidonic acid (AA) [1,2,3]
Piperine Inhibited Platelet Aggregation Induced by Collagen and AA, but Not U46619
Under our experimental condition, cytosolic phospholipase A2 (cPLA2) inhibitor MAFP [38] significantly suppressed cPLA2 activity in both platelets and RAW264.7 cells (Figure 4a,b). These findings suggest that piperine attenuates cPLA2 activity and suppresses AA liberation during platelet aggregation, but not in macrophage inflammation
Summary
Platelet aggregation is a complex, rapidly progressing phenomenon that culminates in the formation of hemostatic plugs and arterial thrombi, which are recognized as potential sources of thromboembolic complications manifesting as atherosclerosis, heart attack, stroke, and peripheral vascular disease.Platelets are activated by various agonists, such as collagen and platelet-activating factor, and undergo a cascade of events that results in the enzymatic metabolism of arachidonic acid (AA) [1,2,3]. Activated macrophages participate in the inflammatory response by, among other roles, producing eicosanoid pro-inflammatory mediators through the stimulation of the same AA metabolic cascade that controls the platelet aggregation. Recent studies have demonstrated that piperine possesses anti-inflammatory properties, elicited by the inhibition of PGE2 generation through suppression of COX-2 gene transcription and protein expression [16,17,18,19,20,21,22]. With regard to putative anti-platelet activity, piperine and piperine-enriched ethanol extract of Piper longum L. have been reported to inhibit platelet aggregation in vitro [23,24,25], but the underlying mechanism is currently poorly understood
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