Tetrahydrocurcumin Downregulates MAPKs/cPLA2 Signaling and Attenuates Platelet Thromboxane A2 Generation, Granule Secretion, and Thrombus Growth

Abstract

Platelet granule secretion plays a key role in atherothrombosis. Curcumin, a natural polyphenol compound derived from turmeric, exerts multiple biological activities. The current study sought to investigate the efficacy of tetrahydrocurcumin (THC, the major active metabolite of curcumin) on platelet granule secretion in vitro and thrombus formation in vivo. We found that THC significantly attenuated agonist-induced granule secretion in human gel-filtered platelets in vitro, including CD62P and CD63 expression and platelet factor 4, CCL5, and adenosine triphosphate release. These inhibitory effects of THC were partially mediated by the attenuation of cytosolic phospholipase A2 (cPLA2) phosphorylation, leading to a decrease in thromboxane A2 (TxA2) generation. Moreover, the MAPK (Erk1/2, JNK1/2, and p38 MAPK) signaling pathways were downregulated by THC treatment, resulting in reduced cPLA2 activation, TxA2 generation, and granule secretion. Additionally, THC and curcumin attenuated murine thrombus growth in a FeCl3-induced mesenteric arteriole thrombosis model in C57BL/6J mice without prolonging the tail bleeding time. THC exerted more potent inhibitory effects on thrombosis formation than curcumin. Through blocking cyclooxygenase-1 activity and thus inhibiting platelet TxA2 synthesis and granule secretion with aspirin, we found that THC did not further decrease the inhibitory effects of aspirin on thrombosis formation. Thus, through inhibiting MAPKs/cPLA2 signaling, and attenuating platelet TxA2 generation, granule secretion, and thrombus formation, THC may be a potent cardioprotective agent.

The Antioxidant, Anti-Platelet and Anti-Coagulant Properties of Phenolic Compounds, Associated with Modulation of Hemostasis and Cardiovascular Disease, and Their Possible Effect on COVID-19

“…Results of Chapman et al [ 66 ] also demonstrated that the major plasma metabolite of curcumin—tetrahydrocurcumin may modulate hemostasis: platelet aggregation and coagulation process. Li et al [ 67 ] suggest that anti-platelet action of tetrahydrocurcumin includes inhibiting MAPKs/phospholipase A 2 (PLA 2 ) signaling, attenuating platelet TXA 2 generation, and granule secretion.…”

Nutrition Phytochemicals Affecting Platelet Signaling and Responsiveness: Implications for Thrombosis and Hemostasis

“…98,99 Regarding quantitative or qualitative platelet changes and hemostasis (bleeding risk), only few information is available, limited to animal studies. Indications on an increased tail bleeding time were made for animals treated with diallyl trisulfides, 121 curcumin, 40,122 epigallocatechin, 123 nobiletin, 124 or chlorogenic acid. 51 Few other papers indicated that phytochemicals can inhibit thrombus formation and platelet function without increased tail bleeding times, i.e., for quercetin, 125 myricetin, 72 and delphinidin glucoside.…”

Sulforaphane attenuates glycoprotein VI-mediated platelet mitochondrial dysfunction through up-regulating the cAMP/PKA signaling pathway in vitro and in vivo

“…Plasma-free gel-filtered platelets were isolated from PRP by using a Sepharose 2B column in PIPES buffer (4 mM KCl, 5 mM PIPES, 1.37 mM NaCl, 0.1% (w/v) glucose, pH 7.0) according to our previously described methods. 20,23,24…”

“…Plasma-free gel-filtered platelets were isolated from PRP by using a Sepharose 2B column in PIPES buffer (4 mM KCl, 5 mM PIPES, 1.37 mM NaCl, 0.1% (w/v) glucose, pH 7.0) according to our previously described methods. 20,23,24 After eight hours of fasting, C57BL/6J mice were anesthetized by intraperitoneal injection of 10% chloral hydrate (0.02 mL per g body weight). Murine blood was collected from anesthetized mice via cardiac puncture and drawn into a tube containing 3.8% acid citrate dextrose (ACD, 100 mM dextrose, 75 mM trisodium citrate and 38 mM citric acid).…”