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.

Keywords

tetrahydrocurcumin - platelet granule - cytosolic phospholipase A₂ - thromboxane A₂ - thrombosis

^* Weiqi Li and Yongjie Ma contributed equally to this work.

Publikationsverlauf

Eingereicht: 03. März 2021

Angenommen: 19. Juli 2021

Artikel online veröffentlicht:
24. August 2021

• References

• 1 Leong DP, Joseph PG, McKee M. et al. Reducing the global burden of cardiovascular disease, part 2: prevention and treatment of cardiovascular disease. Circ Res 2017; 121 (06) 695-710
• 2 Xu XR, Zhang D, Oswald BE. et al. Platelets are versatile cells: new discoveries in hemostasis, thrombosis, immune responses, tumor metastasis and beyond. Crit Rev Clin Lab Sci 2016; 53 (06) 409-430
• 3 Joshi S, Banerjee M, Zhang J. et al. Alterations in platelet secretion differentially affect thrombosis and hemostasis. Blood Adv 2018; 2 (17) 2187-2198
• 4 Bakogiannis C, Sachse M, Stamatelopoulos K, Stellos K. Platelet-derived chemokines in inflammation and atherosclerosis. Cytokine 2019; 122: 154157
• 5 Palabrica T, Lobb R, Furie BC. et al. Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets. Nature 1992; 359 (6398): 848-851
• 6 Blair P, Flaumenhaft R. Platelet alpha-granules: basic biology and clinical correlates. Blood Rev 2009; 23 (04) 177-189
• 7 McNicol A, Israels SJ. Platelet dense granules: structure, function and implications for haemostasis. Thromb Res 1999; 95 (01) 1-18
• 8 Yadav S, Storrie B. The cellular basis of platelet secretion: emerging structure/function relationships. Platelets 2017; 28 (02) 108-118
• 9 Azorsa DO, Hyman JA, Hildreth JE. CD63/Pltgp40: a platelet activation antigen identical to the stage-specific, melanoma-associated antigen ME491. Blood 1991; 78 (02) 280-284
• 10 Ya F, Xu XR, Shi Y. et al. Coenzyme Q10 upregulates platelet cAMP/PKA pathway and attenuates integrin αIIbβ3 signaling and thrombus growth. Mol Nutr Food Res 2019; 63 (23) e1900662
• 11 Martínez-González MA, Gea A, Ruiz-Canela M. The Mediterranean diet and cardiovascular health. Circ Res 2019; 124 (05) 779-798
• 12 Mozaffarian D. Dietary and policy priorities for cardiovascular disease, diabetes, and obesity: a comprehensive review. Circulation 2016; 133 (02) 187-225
• 13 Novaes JT, Lillico R, Sayre CL. et al. Disposition, metabolism and histone deacetylase and acetyltransferase inhibition activity of tetrahydrocurcumin and other curcuminoids. Pharmaceutics 2017; 9 (04) 45
• 14 He H, Luo Y, Qiao Y. et al. Curcumin attenuates doxorubicin-induced cardiotoxicity via suppressing oxidative stress and preventing mitochondrial dysfunction mediated by 14-3-3γ. Food Funct 2018; 9 (08) 4404-4418
• 15 Man S, Yao J, Lv P, Liu Y, Yang L, Ma L. Curcumin-enhanced antitumor effects of sorafenib via regulating the metabolism and tumor microenvironment. Food Funct 2020; 11 (07) 6422-6432
• 16 Li H, Sureda A, Devkota HP. et al. Curcumin, the golden spice in treating cardiovascular diseases. Biotechnol Adv 2020; 38: 107343
• 17 Schneider C, Gordon ON, Edwards RL, Luis PB. Degradation of curcumin: from mechanism to biological implications. J Agric Food Chem 2015; 63 (35) 7606-7614
• 18 Lai CS, Ho CT, Pan MH. The cancer chemopreventive and therapeutic potential of tetrahydrocurcumin. Biomolecules 2020; 10 (06) 831
• 19 Aggarwal BB, Deb L, Prasad S. Curcumin differs from tetrahydrocurcumin for molecular targets, signaling pathways and cellular responses. Molecules 2014; 20 (01) 185-205
• 20 Chen BL, Chen YQ, Ma BH. et al. Tetrahydrocurcumin, a major metabolite of curcumin, ameliorates allergic airway inflammation by attenuating Th2 response and suppressing the IL-4Rα-Jak1-STAT6 and Jagged1/Jagged2 -Notch1/Notch2 pathways in asthmatic mice. Clin Exp Allergy 2018; 48 (11) 1494-1508
• 21 Mayanglambam A, Dangelmaier CA, Thomas D, Damodar Reddy C, Daniel JL, Kunapuli SP. Curcumin inhibits GPVI-mediated platelet activation by interfering with the kinase activity of Syk and the subsequent activation of PLCgamma2. Platelets 2010; 21 (03) 211-220
• 22 Ya F, Tian J, Li Q. et al. Cyanidin-3-O-β-glucoside, a natural polyphenol, exerts proapoptotic effects on activated platelets and enhances megakaryocytic proplatelet formation. J Agric Food Chem 2018; 66 (41) 10712-10720
• 23 Ya F, Li K, Chen H. et al. Protocatechuic acid protects platelets from apoptosis via inhibiting oxidative stress-mediated PI3K/Akt/GSK3β signaling. Thromb Haemost 2021; 121 (07) 931-943
• 24 Yamanaka Y, Sawai Y, Nomura S. Platelet-derived microparticles are an important biomarker in patients with cancer-associated thrombosis. Int J Gen Med 2019; 12: 491-497
• 25 Song F, Zhu Y, Shi Z. et al. Plant food anthocyanins inhibit platelet granule secretion in hypercholesterolaemia: Involving the signalling pathway of PI3K-Akt. Thromb Haemost 2014; 112 (05) 981-991
• 26 Naik MU, Patel P, Derstine R. et al. Ask1 regulates murine platelet granule secretion, thromboxane A₂ generation, and thrombus formation. Blood 2017; 129 (09) 1197-1209
• 27 Ya F, Xu XR, Tian Z. et al. Coenzyme Q10 attenuates platelet integrin αIIbβ3 signaling and platelet hyper-reactivity in ApoE-deficient mice. Food Funct 2020; 11 (01) 139-152
• 28 Xu XR, Wang Y, Adili R. et al. Apolipoprotein A-IV binds αIIbβ3 integrin and inhibits thrombosis. Nat Commun 2018; 9 (01) 3608
• 29 Li Z, Zhang G, Le Breton GC, Gao X, Malik AB, Du X. Two waves of platelet secretion induced by thromboxane A2 receptor and a critical role for phosphoinositide 3-kinases. J Biol Chem 2003; 278 (33) 30725-30731
• 30 Etulain J, Fondevila C, Negrotto S, Schattner M. Platelet-mediated angiogenesis is independent of VEGF and fully inhibited by aspirin. Br J Pharmacol 2013; 170 (02) 255-265
• 31 Cho MJ, Liu J, Pestina TI. et al. The roles of alpha IIb beta 3-mediated outside-in signal transduction, thromboxane A2, and adenosine diphosphate in collagen-induced platelet aggregation. Blood 2003; 101 (07) 2646-2651
• 32 Fälker K, Lange D, Presek P. ADP secretion and subsequent P2Y12 receptor signalling play a crucial role in thrombin-induced ERK2 activation in human platelets. Thromb Haemost 2004; 92 (01) 114-123
• 33 Lucotti S, Cerutti C, Soyer M. et al. Aspirin blocks formation of metastatic intravascular niches by inhibiting platelet-derived COX-1/thromboxane A2. J Clin Invest 2019; 129 (05) 1845-1862
• 34 Fontana P, Zufferey A, Daali Y, Reny JL. Antiplatelet therapy: targeting the TxA2 pathway. J Cardiovasc Transl Res 2014; 7 (01) 29-38
• 35 Patel P, Naik UP. Platelet MAPKs-a 20+ year history: What do we really know?. J Thromb Haemost 2020; 18 (09) 2087-2102
• 36 Moroi AJ, Watson SP. Impact of the PI3-kinase/Akt pathway on ITAM and hemITAM receptors: haemostasis, platelet activation and antithrombotic therapy. Biochem Pharmacol 2015; 94 (03) 186-194
• 37 von Hundelshausen P, Schmitt MM. Platelets and their chemokines in atherosclerosis-clinical applications. Front Physiol 2014; 5: 294
• 38 Pang A, Cui Y, Chen Y. et al. Shear-induced integrin signaling in platelet phosphatidylserine exposure, microvesicle release, and coagulation. Blood 2018; 132 (05) 533-543
• 39 Estevez B, Shen B, Du X. Targeting integrin and integrin signaling in treating thrombosis. Arterioscler Thromb Vasc Biol 2015; 35 (01) 24-29
• 40 Chiang CY, Chien CY, Qiou WY. et al. Genetic depletion of thromboxane A2/thromboxane-prostanoid receptor signalling prevents microvascular dysfunction in ischaemia/reperfusion injury. Thromb Haemost 2018; 118 (11) 1982-1996
• 41 Kang N, Wang MM, Wang YH. et al. Tetrahydrocurcumin induces G2/M cell cycle arrest and apoptosis involving p38 MAPK activation in human breast cancer cells. Food Chem Toxicol 2014; 67: 193-200
• 42 Wu JC, Lai CS, Badmaev V, Nagabhushanam K, Ho CT, Pan MH. Tetrahydrocurcumin, a major metabolite of curcumin, induced autophagic cell death through coordinative modulation of PI3K/Akt-mTOR and MAPK signaling pathways in human leukemia HL-60 cells. Mol Nutr Food Res 2011; 55 (11) 1646-1654
• 43 Adam F, Kauskot A, Nurden P. et al. Platelet JNK1 is involved in secretion and thrombus formation. Blood 2010; 115 (20) 4083-4092
• 44 Nagy Jr B, Bhavaraju K, Getz T, Bynagari YS, Kim S, Kunapuli SP. Impaired activation of platelets lacking protein kinase C-theta isoform. Blood 2009; 113 (11) 2557-2567
• 45 McNicol A, Shibou TS. Translocation and phosphorylation of cytosolic phospholipase A2 in activated platelets. Thromb Res 1998; 92 (01) 19-26
• 46 Vijaya Saradhi UV, Ling Y, Wang J. et al. A liquid chromatography-tandem mass spectrometric method for quantification of curcuminoids in cell medium and mouse plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2010; 878 (30) 3045-3051
• 47 Naito M, Wu X, Nomura H. et al. The protective effects of tetrahydrocurcumin on oxidative stress in cholesterol-fed rabbits. J Atheroscler Thromb 2002; 9 (05) 243-250
• 48 Helson L, Bolger G, Majeed M, Vcelar B, Pucaj K, Matabudul D. Infusion pharmacokinetics of Lipocurc™ (liposomal curcumin) and its metabolite tetrahydrocurcumin in Beagle dogs. Anticancer Res 2012; 32 (10) 4365-4370
• 49 Okada K, Wangpoengtrakul C, Tanaka T, Toyokuni S, Uchida K, Osawa T. Curcumin and especially tetrahydrocurcumin ameliorate oxidative stress-induced renal injury in mice. J Nutr 2001; 131 (08) 2090-2095
• 50 Bolger GT, Licollari A, Tan A. et al. Pharmacokinetics of liposomal curcumin (Lipocurc™) infusion: effect of co-medication in cancer patients and comparison with healthy individuals. Cancer Chemother Pharmacol 2019; 83 (02) 265-275