Novel Antiplatelet Activity of Protocatechuic Acid through the Inhibition of High Shear Stress-Induced Platelet Aggregation

Abstract

Bleeding is the most common and serious adverse effect of currently available antiplatelet drugs. Many efforts are being made to develop novel antithrombotic agents without bleeding risks. Shear stress-induced platelet aggregation (SIPA), which occurs under abnormally high shear stress, plays a crucial role in the development of arterial thrombotic diseases. Here, we demonstrate that protocatechuic acid (PCA), a bioactive phytochemical from Lonicera (honeysuckle) flowers, selectively and potently inhibits high shear (Ͼ10,000 s Ϫ1 )-induced platelet aggregation. In isolated human platelets, PCA decreased SIPA and attenuated accompanying platelet activation, including intracellular calcium mobilization, granule secretion, and adhesion receptor expression. The anti-SIPA effect of PCA was mediated through blockade of von Willebrand factor binding to activated glycoprotein Ib, a primary and initial event for the accomplishment of SIPA. Conspicuously, PCA did not inhibit platelet aggregation induced by other endogenous agonists like collagen, thrombin, or ADP that are important in both pathological thrombosis and normal hemostasis. Antithrombotic effects of PCA were confirmed in vivo in a rat arterial thrombosis model, where PCA significantly delayed the arterial occlusion induced by FeCl 3 . Of particular note, PCA did not increase bleeding times in a rat tail transection model, whereas conventional antiplatelet drugs, aspirin, and clopidogrel substantially prolonged it. Collectively, these results suggest that PCA may be a novel antiplatelet agent that can prevent thrombosis without increasing bleeding risks.

The Cardioprotective Effect of Protocatechuic Acid on Myocardial Ischemia/Reperfusion Injury

“…Stumpf et al (29) reported that PCA significantly inhibited TNF-a-induced expression and release of adhesion molecules, cytokines, and chemokines as well as ADP-induced expression of platelet P-selectin in human vascular endothelial cells. A recent study also demonstrated that the anti-platelet and anti-thrombotic effect of PCA is mediated by selectively inhibiting shear-induced platelet aggregation through the blockade of the interaction between von Willebrand factor (vWF) and platelet receptor GPIb (5). Consistent with these studies, our data showed that PCA could also inhibit the inflammatory response and the enhanced platelet aggregation in MI/R.…”

“…Protocatechuic acid (3, 4-dihydroxybenzoic acid, PCA; Fig. 1), a simple phenolic compound, is plentiful in edible fruits and vegetables and also naturally present in many Chinese herbs such as Salvia miltiorrhiza (3), Sarcandra glabra (4), Lonicera japonica (5), and Hibiscus sabdariffa (6), etc. However, over the past years, little attention has been paid to the beneficial effects of PCA on health.…”

Evaluation of the antiaggregant activity of ascorbyl phenolic esters with antioxidant properties

“…By contrast, this bioactive phytochemical was unable to alter platelet aggregation in response to classical platelet agonists like collagen or Thr, although its effect on ADP-induced aggregation remains controversial [33,43]. Additionally, current evidence supports its beneficial antioxidant effects in endothelial and smooth muscle cells [83], leading to propose this molecule as a possible therapeutic candidate for the treatment of thrombosis and other vascular pathologies, like stroke [31].…”

“…F u r t h e r m o r e , i t h a s b e e n r e p o r t e d t h a t protocatechuic acid is able to reduce platelet aggregation in response to shear stress, since it reduces the von Willebran factor-dependent stimulation of platelets by blocking the glycoprotein Ib, which would avoid platelet interaction with the endothelium, and subsequently, it would also reduce the positive feedback exerted by von Willebrand factor in recruiting the surrounding circulating platelets [33]. By contrast, this bioactive phytochemical was unable to alter platelet aggregation in response to classical platelet agonists like collagen or Thr, although its effect on ADP-induced aggregation remains controversial [33,43].…”

“…They have also been reported to affect platelet function. For instance, gallic acid, caffeic acid, and protocatechuic acid, being the latest found in roselle, onion skin, and mushrooms, showed that antiplatelets effect through altering different platelet signaling pathways [3,11,33,50].…”