Avallable online t www sciencediect.com este : Chinese ScienceDirect Journal of Natural Chinese Journal of Natural Medicines 2013, 1(4): 0345-0353, Medicines Green tea catechins: defensive role in cardiovascular disorders Pooja Bhardwaj, Deepa Khanna’ Cardiovascular Pharmacology Division, Deparinsent of Pharmacology, Rajendra Insinte of Telology ad Sefences, Sia, India Available online 20 July 2013 [ABSTRACT] Green tea, Camellia sinensis (Theaceae), a major source of Mavonoids such as catechins, has recently shown multiple ‘cardiovascular health benctits ttongh various experimental an clinical studies. These studies suggest that ere tea catechins prevent the incidence of detrimental cardiovascular events, and also lower the cardiowasclar mortality rate. Catchins resent in green tea have the ability to prevent atherosclerosis, hypertension, endothelial dysfunction, ischemic heart diseases, cardiomyopathy, cardiac hyper ‘wophy and congestive heat fulure by decreasing oxidative sess, preventing iflammatory eveuts, reducing platelet agarezation and dualking the proliferation of vascular stnooth aausle cells Catechins afford a anti-oxidant effect by inducing aut-oxidaa! ez) tes, inkibiting pro-oxidant eazyanes and scavenging fee radicals. Catechis present aut-inflammatory activity through the inbibition of olecles. Grosa ten catechins interfere with vascular ‘rauscriptioal factor NF-xE-mesiated production of cytokines and adhesion row factors and thus inhibit vaseular smooth muscle cell proliferation, and also inhibit thombogenesis by suppressing platelet adhesion, Aditionaly catechins could protect vasenlar endotlil cells and enhance vascular itepity and regulate blood pressure, In this review varios experimental ad elinical studies igeesting the role of green fen catechins agninst the maskets of eadiovaseular slisorders andthe undevlying mechanisms fr these actions are discussed. IKEY WORDS] Greca tea catechins: Reactive oxygen species Vascular eel aesion molecule covders [CLC Number] R965 Nitric oxide; Cardiovascular di [Document code] A i fle 1D] 1672-3651(2013)04-0345-009 dates, lipids, such as linoleic and clinolenic acids, sterols, ‘vitamins (B, C, ), plamens, such as chlorophyll and earo- tenoids, volatile compounds, suchas aldehydes, and minerals ‘and trace elements "!. The major components of green tea are the polyphenols, which represent 36% dry weight of green tea, Polyphenols present in groen tea are flavonoids. fermented grcen tea contains more than 80% of flavonoids “while fermented black tea has only 20°-30%% ofthis phyto- constituent “!, The major flavonoids of green tea are cate which include (-)-epicatechin (EC), (C-epicatechin-3-gallate (ECG), ()}{EGC) and (-epigallo- catechin--gallate (EGCG), (Pcatechin (C), (P+gallocatechin (GO), (=)catechin gallate (CG), and (+}gallocatechin gallate (GCG) "4 EGCG is the most abundant green tea catechin (GTC), snd is thought to be responsible for the majority of the biological activities of green tea". Green tea contains 21 img'L of C, 98 mg'L™ of EC, 90 mg: L™ ECG 411 mgL* 2013, EGC, and 444 meL" EGCG "Green tea consumption is 1 Introduction ‘Teas one ofthe mos Widely consumed beverages inthe ‘world. The increasing heals benefits of tea has led to the ineluson of ea extracts in ditay supplements and funtion- al foods. Green tea (non-oxidized), Oolong ten (partially ‘oxidized, and Black ta (oxidized), three major categories of tea obtained from the plant Comet sinensis (L.) Kuntze belonging to the family Theacese.difer in terms of their manufacturing and chemical composition "Tea cate- chins esert a variety of physiological actions, which may be primarily responsible for the health benefits of greea ta ‘There is surfeit of htezatue which coreelats the potential of| ‘green tea catechins with their chemistry. Green tea i come ised of proteins, including enzymes, amino acids, carbohy= chins, [Received on] 19-Max: [-Corresponding author] Decpa Khanna: PhD. Te: 91-9416880005, nmi Tdeepad@ gmail com These authors have no conflict of interest odaclave Copytigt © 2013, China Pharmaceutical Univesity Published by Elsevier BV All rights reserved associated with a variety of physiological functions, which ‘may be primarily responsible for possible beneficial effects. The versatility of catechins and their active metabolites for potential therapeutic interventions is due to the diverse ac-Pooja Bhat), ea. / Chinese Jonna of Nanwal Madicies 2013, (4). 345-383 tions being performed at diferent sites. Many clinical and epidemiological studies have examined these actions of ea- techins in the form of anti-carcinogenic ©), anti-tumorigenic 9), utiamutageic , ant-diabetc ©) and anti-obesity ef- Cardiovascular disease isthe singe largest contributor to lobal mortality today. and will continue to dominate mortal- ity wends i the future"! Quite a significant amount of te- search has already been carried out in exploring various syn- thetic and plant-based interventions which ean prevent this disorder In this direction, some epidemiological and review studies have reported the positive relationship between GTC intake and reduced cardiovascular disorders? The mul- tiple mechanisms undergone by GTC for the prevention of coronary heart disease involve its anti-sidative, ane tisinflammatory, anti-proliferative, anti-platelet, and ane tithrombogenic effects "| In this review, the available data onthe effest of green tea on cardiovascular performance and risk are presented, Oxidative sess inflammation, vas- cular endothelial function, proliferation and platelet agerega- tion, and their management by green tea will be discussed 2. Effect of GTC on Cardiovascular Risk Factors 21 Anica activity ‘Oxidative stess plays a crucial roe inthe progression of various cardiovascular diseases, inchuding atherosclerosis, hypertension, endothelial dysfunction, ischemic heart diseas- «s, cardiomyopathy, cardiac hypertrophy and congestive heart failure, Increased formation of reactive oxygen species (ROS) andlor decreased antioxidant enzymes indicate oxidative stress in cardiac and vascular myocytes, Oxidative stress-medinted ROS causes rapid depolarization of mito- chondrial inner membrane poteatial and subsequent impait- ment of oxidative phosphorylation. Damaged mitochondria produce ROS, especially in the form of the superoxide anion £) and hydrogen peroxide (H,0,), which further propagate ROS generation, Moreover the increased generation of ROS is due to its increased secretion by white blood cells, endo- thelial dysfunction, and auto-oxidation of catecholamines, as well as exposure to radiation or air pollutants "=". Nox! Nox2, and Nox 4 family members of NADPH oxidase. xan- thine oxidase, eyelooxygenase, lpoxygenases. and uncoupled nitric oxide synthase form and propagate ROS generation "1 Mamumalian cells ae equipped with a varity of antioxi- dant enzymes to control ROS production and its fimther propagation, Superoxide dismutase (SOD), catalase (CAT) lutathione peroxidase (GPX), and glutathione reductase (GSR) are the major enzymes that represent a coordinated ‘operating network of defenses against oxidative stress induced tissue damage“, Depletion of these antioxidant reserves, cither due to ROS or due to the exhaustion andor changes in gene expression, plays a crucial role in vascular bnormalities GTC axe important antioxidants, which can reduee oxid- ative stress mediated lipid peroxidation, endothelial dysfune- ton and improves antioxidant defense "Heim ea demon- strated that catechins uninterrupted produced their antioxi- dant effects by seavenging ROS, cheating redox-ative tran sition metal ions, and inhibiting lpi peroxidation "EGCG, at different doses, educed lipid peroxidation !. However, catechins also function cireuitously by inhibiting the re- dox-sensitive tanscrption factors, nuclear factor-kappaB (NF-xB) and activator protein-1 responsible for oxidative stress, Further, GTC manage the generation of ROS by inhi- biting “pro-oxidant” enzymes, such as inducible nitric oxide synthase (INOS), lipoxygenase, cyclooxygenase and xanthine oxidase, and by inducing antioxidant enzymes, such as SOD, CAT and GPX "1 EGCG protects heart against doxorubi- cininduced myocyte injury’ by improving Cat” handling through scavenging reactive oxygen species "!. Green tea extract prevented the development of atherosclerosis in apo- lipoprotein E-deficient mice through its potent ani-oxidative activity °". (Fig.l) The above evidence suggests thatthe antioxidant properties of the catechins contributes to the car Aioproectve activity of green tea 2.2. Ami-inflammatory activity Atherosclerosis is normally considered a bland lipid sto- ‘rage disease, but actually involves an on-going inflammatory response, Inflammation-induced monocyte adhesion 10 endothelial cells (ECS), followed by transmigration into the subendothelial intima, is one ofthe key events in the devel- opment of atherosclerosis" mn normal conditions, ECs, which form the innermost surface of the artery wal, resist adhesion by leukocytes However, triggers of atherosclerosis, such as a high- saturated-fat diet, smoking, hypertension, hyperglycemi obesity, and insulin resistance, can initiate the expression of adhesion molecules by ECs, thus allowing the attachment of leukocytes to the arterial wall PY, NF.xB regulated intercellular adhesion molecule-I ICAM1) and vaseular cel adhesion molecule-1 (VCANE-1) play pivotal role in the binding of leukocytes tothe sites of inflammation”. Once adhered to the endothelium, the leukocytes penetrate into the intima, Chemoattactant molecules, such as monocyte che- moattractant protcin-1 (MCP-1), interleukin-8 (IL-8) and E-selectin, are responsible for the direst migration of mono- eytes into the intima atthe sites of lesion formation > *! Further, macrophage coloay-stimulating factor (MC-SF) also contributes to the transmigration of monocytes into the intima Once resident inthe arterial wall, the blood- derived inflammatory cells participate in, and perpetuate, 4 local inflammatory response. The potent pro-inlanamat eytokine, tumor necrosis factor-alpha (TNF-<). plays 8 paogeic role in chronic inflammation and ahees- GTC prevent inflammation-mediated atherosclerosis byPooja Bhat), ea. / Chinese Jonna of Nanwal Madicies 2013, (4). 345-383 suppressing leukoeyte adhesion 10 the endothelium and is Fig. Anthoxidant defense mechanism of catechins Dotted anow indicates inhibition, while the siuplearows indicate setvation. Catchins activate antioxidant enzynes such as Superoxide dim tase (SOD), Catalase (CAT), and Glutathione peroxidase (GPX), and ibibit tho enzymes which are responsible for oxidative sess such as [NADPH oxidase, lipoxy sense, eyelooxygense, xanthine oxidase, and iNOS (inducible nite oxide synthase) subsequent transmigration! Catechins induce an an- tiinlammatory effect by the suppression of several inflim- ratory fhetors, including NF-sB, eytokines, and adhesion molecules"), Suzuki ea. confirmed that GTC attenuated the development of the systemic inflammatory diseases with the suppression of the inflammatory factors ©! Catehins reduced the expression of cytokines. NF-xB, ICAM-1, and ‘TNF-a responsible for inflammation, and suppress myocardi- al inflammation in rats ", Further, GTC can suppress lene kkoeyte adhesion to ECs. EGCG and ECG at different doses prevented the expression of VCAMEL, and thus reduced the leukocyte adhesion to ECs") Liang e al, demonstrated that EGCG treatment could significantly reduce monocyte che- ‘moatractant protein-1 (MCP-1) responsible for inflammation "91 (Fig. 2), Thus GTC prevents inflammation-induced atherosclerosis, 23 Effect of GIC on vascular endothelial dysfunction ‘The vaseular endothelium i a simple monolayer of inner blood vessels that separates blood and peripheral tissues, and ‘maintains homeostasis by regulating vascular tone “. The ECs maintain vaseular tone by balancing vasoconsticting substances, sich as endotheline (ET-1), prostaglandins, an- siotensin Ht (Ang-I) and vasoilating substances, such as nitric oxide (NO), prostayclin and various endothelium derived hyperpolarizing factors (EDHFs) "Vascular endothelial dysfunction (VED) is a systemic. pathological state of the endothelium, and can be broadly defined as an imbalance between these vasodilators and vasoconstritors VED is involved in the pathogenesis of various cariovascu- Jar disorders such as hypertension, atherosclerosis, coronary artery diseases, diabetes mellitus and nephropathy ‘Nitric oxide (NO), an endothelium-derived relaxing fe tor (EDRF), is generated during the conversion of L-arginine to L-citrlline by endothelial NO synthase (eNOS) in the presence of various substrates and co-fators "NO is a fundamental determinant for maintaining the vascular fune- tions. The phosphatidylinositol 3-kinase (PI3-K) pathway plays a key role in maintaining vascular function by actvat- ing serine threonine protsin kinase (protcin kinase BVAK?) which subsequently enhances eNOS phosphoryla- tion/ativation and NO production VED occurs as a result of high oxidative stress, down regulation and innctiva- tion of eNOS, and diminished production and bioavailability of NO™, [NO, produced by green tea catechins though the activa tion of eNOS enzyme, has the ability to improve vascular endothelial dysfunction. EGCG is capable of modulating ROS production and eNOS activation, thereby increasing the production of NO "EGCG produced vasorelaxation in tat aortic rings by activating eNOS through the PISK/Akt path- way in ECS 8 Further, EGCG was shown to produce NO fiom endothelium using, PI-Kinase-dependent pathay in spontaneously by =) Catechins also stimu lated the produetion of prostacyclin in bovine aortic ECs Asymmetric dimethylarginine (ADMA) competes with arginine and, by inhibiting nitric oxide symthase, reduces NO production in the vascular wall “). EGCG preserves endothelial function by reducing the endogenous ADMAPooja Bhat), ea. / Chinese Jonna of Nanwal Madicies 2013, (4). 345-383 level 9 Consumption of green tea in drinking water atte Penetration of Jeukocyes ino intima by NCP-11L-8 & E-sdloctin uated blood pressure in stroke-prone spontaneously hyper- Endotatal Fig. 2 Effect of catechins against inflammatory factors Doe rows india inhibition, while simple arows indicate activation, NF-xB regulated intercellular adhesin ‘vascular cll adhesion molecule-1 (VCAN-1 pay a pivotal role in binding of leukocytes tothe endotela cell (EC) which are further pencated into itina by monoeyte ebemo-atectant potent (MCP-1),iteleukin-8 (IL-8) and E-selectin, and Jet to illamation, Catechins could inhibit al these steps of nammation tensive rats" (Fig, 3) Improvement in vascular endothelial dysfunction might potentially contribute to the beneficial cffets of GTC in the treatment of patents with hypertension. 24 Anvi-protiferative activity In addition to inflammation, a key process of atheros: lerosis involves the proliferation of vaseular smooth muscle cells (VSMCS) "In carly atherosclerosis, VSMCs may contribute to the development of the atheroma through the production of pro-inflammatory mediators, such 5 monocyte chemoattractant protein 1 (MCP-1), vascular cell adhesion molecule (VCAM) and matrix metalloproteinases (MMPs) "Fibroblast growth factor. released from dying vascular eels, can initiate proliferation, while plate- letderived growth factor (PDGF) may induce subsequent migration, as well as proliferation, of VSMCs towand the intima ©, Ang IL is highly involved in the proliferation of “VSMC that result in atherosclerosis GTC produce an anti-proliferative effect which may be associated with the reduced risk of cardiovascular diseases, CCatechins inhibited thrombin-induced VSMCS invasion by preventing matrix metalloproteinases-2 (MMP.2) expression and contributed to a protective atherosclerotic effect [EGCG treatment has been shown to arest VSMCs in the Gy phase of the cell eyele by down-regulating important cell «yele regulators, such as eyelins/eyelin-dependent kinases! Ahn er al. demonstrated that 80% ofthe proliferative eect of PDGF-BB (homodimeric form of PDGF) of vascular smooth molecule (CAM) and muscle cells was eliminated after EGCG treatment Proliferation induced by advanced glycation end products (AGES) in VSMCs are reverted by GTC"). EGCG is ca pable of suppressing ghucase accelerated VSMCs prolifera tion by up-regulating protein kinase-C (PKC) "1. Further, ‘eatechins can also inhibit VSMCs proliferation vin the inhibi- tion of the Ang U-stimulated activation of the mito- get-sctivated protein kinase pathway “, Collectively, the above studies suggest that GFC can modulate the responsible for VSMCs proliferation, 28. Amiplatelet and am-thromboric activity Platelet activation and aggregation ae hallmarks of cat diovascular diseases, such as myocardial infarction and sitoke "Plaque mupture or damage to the vascular endo- thelial layer by any injury eauses adhesion of platelets tothe suibendothelial matrix: platelets become activated, and then ‘rapidly aggregate to form a prothrombotic surface that pro- ‘motes clot formation and subsequently vascular occlusion. Multiple pathways, including those activated by adenosine diphosphate (ADP), thromboxane A2 (TXA2), epinephrine, serotonin, collagen, and thrombin are involved in platelet activation "9. Evidential records suggest that GTC are ant-thrombotic in action. Anfi-platclet activity mediated by EGCG in dose-dependent manner prevents death caused by tombosis in mice "Yang er af also concluded their sty ‘with antiplatelet and antithrombotic effects of catechins in diabetic rats "Arachidonic acid and TXA2 symthasePooja Bhat), ea. / Chinese Jonna of Nanwal Madicies 2013, (4). 345-383 ‘generated thromboxane A2 was inbibited by green tea cate- arginine I = +t =e chins "Intracellular caleium concenteation promotes Fig. 3 Improved NO production by catechins through eNOS activation [itie oxide (NO) is generated during te conversion of L-nginine fo L- rule by endothelial NO syntase (eNOS). Asymmetric dimethyl sine (ADMA) eompetos wih L-arginine and, by inhibiting eNOS, produces reactive exygen species (ROS) in the vascula wall. Catechios i ‘reas NO production by activating €NOS and inking ADMA. fibrinogen binding to human platelet surfice glycoprotein Iihlla (GP IThla) complex via inereasing inositol 1, 4 Strphosphate (193) formation and depleting Ca™-ATPase GTC supplementation inhibited the eyteplasmic calcium increase, thereby showing their antiplatelet effect by reverse ing the above process". 3 Clinical Studies Pertaining to the Potential of GTC in Cardiovascular Disorders Strong data ftom in vitro and in vivo studies, demonstrate the benefits of green tea, rich in catechins, om several me- chanisms contributing to eardiovascular health. This eonchte siom is substantiated by human studies, whic hivhlights the contribution of GTC in supporting a healthy cardiovascular system. A number of potential outcomes adresse in various clinical studies revealed that green tea consumption benefits the cardiovascular system. The recent Ohsaki study, dane on 40 530 Japanese individual, revealed that those Japanese consuming five or more cups of green tea per day showed 12% reduetion in total and a 26% reduction in cardiovascular ‘mortality when compared to those who were consming less than 1 cup per day "7. The main outcome of clinical studies conducted on five healthy non-smokers was that green tea is cfficent in protecting low density lipoprotein from oxidation driven by peroxyl and fey radicals, respectively Green ten consumption in a concentration of > 800 mL over a 4+-month period improved endothelial function and other cardiovascular tsk factors in a Tapanese population 9. Kim ct al. reported that endothelial function significantly ine proved with improvement of flow mediated dilatation in 20 ‘young smokers who consumed 8 g green ten per day (3.2% EGCG) over a period of two weeks!) GTC also produced antatherosclerotic effects on dysfunctional vessels in smokers through increasing the level of NO ©. Recently: Wong ea reported that consuming more than 1 cup day of areen tea reduces the risk of developing coronary axtery dis ease by 10°6 1. Clinical use of green ta indicates tha its consumption significantly decreased the urinary conoenta- tion of 8so-prostaglandin-F2a, an index of oxidative stress and reversed endothelial dysfunction in healthy smokers Ex no study demonstrated that LDL oxidation, arsk factor for atherosclerosis, was inhibited by 3.9% and by 98% ater 12h incubation of human LDL and aortic endothelial cells ‘with 0.08 and 5 ppm green tea extracts respectively. Oxi dized LDL levels were sianifcantly reduced in subjects con- suming 600 mL. green ta, containing $2 g tea solids daly for 4 weeks I, Evidential studies suggest that consumption of four or more cups of green tea a day exhibited an inverse association with coronsey atherosclerosis among. Japanese sen and women 1 EGC reduced IL-8 production i human ECS, and thus can seduce inflammation induced atheroselero- sis Clinical studies also demonstrated that a population suf. fering from hypertension benefited from a high intake of sreen tea. Groen tea is beneficial for lowering sortie sttiness and wave telecon the parameters which lead to hyperten- sion. In non-babitual tea dvinkers, the risk of developing lbypertension decreased by 46% for those people who drank 120-899 mLday, and tis was further reduced by 65% for those who drank 600 ml‘day’ ar more, Studies conducted bby Sano er a. and Sasaziki er of. demonstrated that srcen tea intake lowers the incidence of coronary artery disPooja Bhat), ea. / Chinese Jonna of Nanwal Madicies 2013, (4). 345-383 ‘eases, Furthermore, daily consumption of more than four ‘cups of green tea significantly reduced total cholesterol LDL-cholesterol and wiglyeerides, and improved protective HDL cholesterol "9 4 Bioavailability of GEC How mach green ten does a person need to dink to reap its health benefits? The issue is the poor bioavailability of GTC, unfortunately, which is comelated with ther therapeutic cffects, and is the major concem for researchers. All of the catechins are rapidly absorbed and widely distributed after ingesting a cup of green tea 8" As the catechins are metabo- lized through methylation (EGCG) ©, or comiugation with hucuronide and/or sulfate groups (all catechins except EGCG), the ability of ftee catechins to produce thei bio- logical actions is educed. Other reasons may be the vatiation ‘of contents fiom the actual claim mentioned onthe masketed products "thas been reported in clinical study that the plasma concentration of catechins in healny individuals ac- counts for only 0.2% to 2% of the ingested amount after around 90 min, which is relatively very low | This biow availabilty issue must be overcome to optimize its benefits, In this regard, Chow eal reported thatthe plasma concen- tration of eatechins can be increased 3 to 4 times by ingesting the drug affer an ovemight fasting", which suggests that the bioavailability of eatechins can be improved § Conclusions and Future Direction ‘Overall. it is concluded thatthe intake of green tea which provides sulficient catechins can have beneficial effects agninst cardiovascular disorders in animals and humans. Green tea catechins exert a variety of beneficial metabolic effects by influencing the markers such as oxidative stress, inflammation, proliferation, and platelet aggregation. Ale ‘though, GTC is beneficial in improving endothelial dysfune- tion, the postive effects of green tea catechins on eardiowas- cular system need further attention, Studies should be eared ‘out on the cateciin metabolites which are reported to be bio- logically active, but whose vascular effects are unknown, In addition, the structural aspects, as well asthe bioavailability criteria of GTC, should be further explored, which may lead to clinically relevant strategies to prevent and treat vascular diseases Abbreviations ADMA, Asymmetric dimethylarginine; AGEs, Advanced lycation end products; Ang-II, Angiotensin I; CAT, Cata- lase; EC, (-)-Epicatechin: ECG (-)-Fpicatechin-3-gallate ECS, Endothelial cells; EDHFS, Endothelium-derived hyper= polarizing factors: EDRF, Endothelium-derived relasaing factor, EGC, (-}Epigallocatechin; EGCG, (-)-Bpigallocatechin-3-gallate; eNOS, Endothelial NO syn- thase; ERK1/2, Extracellular regulatory kinase 1/2; ET-L Endothelin-l; GPX, Glutathione peroxidase: GSR, Gluta- thione reductase: GTC, Green tea eatechins; ICAM-1, Inter- cellular adhesion molecule-1; IL-8, Interleukin-8; iNOS, Inducible nitric oxide synthase: MCP-1, Monocyte chemoat- tractant protein-l; MC-SF, Macrophage colony-stimulating factor; MMPs, Matrix metalloproteinases; NADPH, Nicoti- rnamide adenine dinucleotide phosphate, NF-xB, Nuclear fctor-kappa B, NO, Nitric oxide: PDGF, Platelet-derived growth factor: PIS-K, Phosphatidylinositol 3-kinase; PKC. 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