Cardioprotective effect of green tea and green coffee extract as metformin’s add-on to prevent cardiac fibrosis in a rat model of metabolic syndrome

Year 2024, Volume: 28 Issue: 1 , 16 - 28 , 28.06.2025

Indah Nur Chomsy , Mohammad Saifur Rohman Husnul Khotimah Nashi Widodo Nur Ida Panca Nugrahini

https://izlik.org/JA56KJ83NU

Abstract

Metabolic syndrome (METS) is a cluster of risk factors contributing to cardiovascular disease (CVD) development. Agonist-related hypertension and obesity may occur due to excess cardiac pressure caused by increased systemic blood pressure. In addition, METS also enhances the progression of cardiac remodelling through several cardiac fibrosis-related genes. METS treatment is managed using metformin as a glycemic control agent, often given with other complementary agents. This study investigates the effect of green tea and green coffee extract therapy as an add-on to metformin in preventing cardiac organ dysfunction and overexpression of cardiac fibrosis biomarkers in the METS rat model. METS model rats were divided into five groups. The rats' blood pressure, flow, and volume are measured using a non-invasive tail-cuff sphygmomanometer. After nine weeks of treatment, the heart was isolated for measurement of angiotensinogen receptor 1 (ATR1), transforming growth factor β (TGFβ), and collagen type 1 (COL1A1) gene expression by reverse-transcriptase PCR. This study found that there was a significant improvement in blood pressure, increased tail blood flow, and volume (p-value<0.05) and decreased ATR1, TGFβ, and COL1A1 gene expression (p-value=0.000) in the green tea-green coffee and metformin (COMB) therapy group. The correlation analysis results show a positive linear relationship between SBP, DBP, TBF, AT1R, TGFβ, and COL1A1. This study found that green tea and green coffee extract therapy as an add-on to metformin could prevent cardiac dysfunction by improving blood pressure, flow and volume, reducing overexpression of ATR1, TGFβ, COL1A1 gene expression that is related to cardiac fibrosis in the METS rat model.

Keywords

metabolic syndrome , fibrosis , systolic blood pressure , collagen-1 , angiotensin receptor 1

References

• [1] National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106(25):3143-3421.
• [2] Centers for Disease Control and Prevention (CDC) Division of Diabetes Translation. 2017. https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf. (accessed on 18 January 2023).
• [3] GBD 2015 Obesity Collaborators; Afshin A, Forouzanfar MH, Reitsma MB, Sur P, Estep K, Lee A, Marczak L, Mokdad AH, Moradi-Lakeh M, Naghavi M, Salama JS, Vos T, Abate KH, Abbafati C, Ahmed MB, Al-Aly Z, Alkerwi A, Al-Raddadi R, Amare AT, Amberbir A, Amegah AK, Amini E, Amrock SM, Anjana RM, Ärnlöv J, Asayesh H, Banerjee A, Barac A, Baye E, Bennett DA, Beyene AS, Biadgilign S, Biryukov S, Bjertness E, Boneya DJ, Campos-Nonato I, Carrero JJ, Cecilio P, Cercy K, Ciobanu LG, Cornaby L, Damtew SA, Dandona L, Dandona R, Dharmaratne SD, Duncan BB, Eshrati B, Esteghamati A, Feigin VL, Fernandes JC, Fürst T, Gebrehiwot TT, Gold A, Gona PN, Goto A, Habtewold TD, Hadush KT, Hafezi-Nejad N, Hay SI, Horino M, Islami F, Kamal R, Kasaeian A, Katikireddi SV, Kengne AP, Kesavachandran CN, Khader YS. Health Effects of Overweight and Obesity in 195 Countries over 25 Years. N Engl J Med. 2017;377(1):13-27. https://doi.org/10.1056/NEJMoa1614362.
• [4] Balistreri CR, Caruso C, Candore G. The role of adipose tissue and adipokines in obesity-related inflammatory diseases. Mediators Inflamm. 2010; 2010: 802078. https://doi.org/10.1155%2F2010%2F802078.
• [5] Boden G. Obesity, insulin resistance and free fatty acids. Curr Opin Endocrinol Diabetes Obes. 2011;18(2):139-143. https://doi.org/10.1097/med.0b013e3283444b09.
• [6] Lee Hewang L, Jose PA. Coordinated contribution of NADPH oxidase- and mitochondria-derived reactive oxygen species in metabolic syndrome and its implication in renal dysfunction. Front Pharmacol. 2021; 12:670076. https://doi.org/10.3389/fphar.2021.670076.
• [7] Díez J. Mechanisms of cardiac fibrosis in hypertension. J Clin Hypertens (Greenwich). 2007;9(7):546-550. https://doi.org/10.1111/j.1524-6175.2007.06626.x.
• [8] Shinde AV, Frangogiannis NG. Fibroblasts in myocardial infarction: A role in inflammation and repair. J Mol Cell Cardiol. 2014; 70C:74–82. https://doi.org/10.1016/j.yjmcc.2013.11.015.
• [9] Cabandugama PK, Gardner MJ, Sowers JR. The renin angiotensin aldosterone system in obesity and hypertension: Roles in the cardiorenal metabolic syndrome. Med Clin North Am. 2017;101(1):129-137. https://doi.org/10.1016/j.mcna.2016.08.009.
• [10] Lee MY, Luciano AK, Ackah E, Rodriguez-Vita J, Bancroft TA, Eichmann A, Simons M, Kyriakides TR, Morales-Ruiz M, Sessa WC. Endothelial Akt1 mediates angiogenesis by phosphorylating multiple angiogenic substrates. Proc Natl Acad Sci U S A. 2014;111(35):12865-12870. https://doi.org/10.1073/pnas.1408472111.
• [11] Chu C, Deng J, Man Y, Qu Y. Green tea extracts epigallocatechin-3-gallate for different treatments. Biomed Res Int. 2017;2017:5615647. https://doi.org/10.1155/2017/5615647.
• [12] Li F, Wang Y, Li D, Chen Y, Qiao X, Fardous R, Lewandowski A, Liu J, Chan TH, Dou QP. Perspectives on the recent developments with green tea polyphenols in drug discovery. Expert Opin Drug Discov. 2018;13(7):643-660. https://doi.org/10.1080/17460441.2018.1465923.
• [13] Prasanth MI, Sivamaruthi BS, Chaiyasut C, Tencomnao T. A review of the role of green tea (Camellia sinensis) in antiphotoaging, stress resistance, neuroprotection, and autophagy. Nutrients. 2019;11(2):474. https://doi.org/10.3390/nu11020474.
• [14] Nagao T, Hase T, Tokimitsu I. A green tea extract high in catechins reduces body fat and cardiovascular risks in humans. Obesity (Silver Spring). 2007;15(6):1473-1483. https://doi.org/10.1038/oby.2007.176.
• [15] Moore RJ, Jackson KG, Minihane AM. Green tea (Camellia sinensis) catechins and vascular function. Br J Nutr. 2009;102(12):1790-802. https://doi.org/10.1017/S0007114509991218.
• [16] Zheng XX, Xu YL, Li SH, Liu XX, Hui R, Huang XH. Green tea intake lowers fasting serum total and LDL cholesterol in adults: a meta-analysis of 14 randomized controlled trials. Am J Clin Nutr. 2011;94(2):601-610. https://doi.org/10.3945/ajcn.110.010926.
• [17] Roberts JD, Roberts MG, Tarpey MD, Weekes JC, Thomas CH. The effect of a decaffeinated green tea extract formula on fat oxidation, body composition and exercise performance. J Int Soc Sports Nutr. 2015;12(1):1. https://doi.org/10.1186/s12970-014-0062-7.
• [18] Mao X, Gu C, Chen D, Yu B, He J. Oxidative stress-induced diseases and tea polyphenols. Oncotarget. 2017; 8(46):81649-81661. https://doi.org/10.18632/oncotarget.20887.
• [19] Onakpoya I, Terry R, Ernst E. The use of green coffee extract as a weight loss supplement: a systematic review and meta-analysis of randomized clinical trials. Gastroenterol Res Pract. 2011;2011:382852. https://doi.org/10.1155/2011/382852.
• [20] Upadhyay R, Mohan Rao LJ. An outlook on chlorogenic acids-occurrence, chemistry, technology, and biological activities. Crit Rev Food Sci Nutr. 2013;53(9):968-984. https://doi.org/10.1080/10408398.2011.576319.
• [21] Manach C, Scalbert A, Morand C, Rémésy C, Jiménez L. Polyphenols: food sources and bioavailability. Am J Clin Nutr. 2004;79(5):727-747. https://doi.org/10.1093/ajcn/79.5.727.
• [22] Cho AS, Jeon SM, Kim MJ, Yeo J, Seo KI, Choi MS, Lee MK. Chlorogenic acid exhibits anti-obesity property and improves lipid metabolism in high-fat diet-induced-obese mice. Food Chem Toxicol. 2010;48(3):937-943. https://doi.org/10.1016/j.fct.2010.01.003.
• [23] Hsu CL, Huang SL, Yen GC. Inhibitory effect of phenolic acids on the proliferation of 3T3-L1 preadipocytes in relation to their antioxidant activity. J Agric Food Chem. 2006;54(12):4191-4197. https://doi.org/10.1021/jf0609882.
• [24] Bassoli BK, Cassolla P, Borba-Murad GR, Constantin J, Salgueiro-Pagadigorria CL, Bazotte RB, da Silva RS, de Souza HM. Chlorogenic acid reduces the plasma glucose peak in the oral glucose tolerance test: effects on hepatic glucose release and glycaemia. Cell Biochem Funct. 2008;26(3):320-328. https://doi.org/10.1002/cbf.1444.
• [25] Jin S, Chang C, Zhang L, Liu Y, Huang X, Chen Z. Chlorogenic acid improves late diabetes through adiponectin receptor signaling pathways in db/db mice. PLoS One. 2015;10(4):e0120842. https://doi.org/10.1371/journal.pone.0120842.
• [26] Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. 2017; 60(9):1577–1585. https://doi.org/10.1007/s00125-017-4342-z.
• [27] Kwan HY, Hribal ML, Thompson MD, Guo Y, Lv Z. Metformin and its benefits for various diseases. Front Endocrinol. 2020; 1: 191. https://doi.org/10.3389/fendo.2020.00191.
• [28] Vial G, Detaille D, Guigas B. Role of mitochondria in the mechanism(s) of action of metformin. Front Endocrinol. 2019;10:294. https://doi.org/10.3389/fendo.2019.00294.
• [29] Rochlani Y, Pothineni NV, Kovelamudi S, Mehta JL. Metabolic syndrome: pathophysiology, management, and modulation by natural compounds. Ther Adv Cardiovasc Dis. 2017;11(8):215-225. https://doi.org/10.1177/1753944717711379.
• [30] Alshehri AM. Metabolic syndrome and cardiovascular risk. J Family Community Med. 2010;17(2):73-78. https://doi.org/10.4103/1319-1683.71987
• [31] Iida K, Tani S, Atsumi W, Yagi T, Kawauchi K, Matsumoto N, Hirayama A. Association of plasminogen activator inhibitor-1 and low-density lipoprotein heterogeneity as a risk factor of atherosclerotic cardiovascular disease with triglyceride metabolic disorder: a pilot cross-sectional study. Coron Artery Dis. 2017;28(7):577-587. https://doi.org/10.1097/MCA.0000000000000521.
• [32] Bajaj A, Xie D, Cedillo-Couvert E, Charleston J, Chen J, Deo R, Feldman HI, Go AS, He J, Horwitz E, Kallem R, Rahman M, Weir MR, Anderson AH, Rader DJ; CRIC Study Investigators. Lipids, apolipoproteins, and risk of atherosclerotic cardiovascular disease in persons with CKD. Am J Kidney Dis. 2019;73(6):827-836. https://doi.org/10.1053/j.ajkd.2018.11.010.
• [33] Chopra Arun K. Metabolic syndrome or insulin resistance: Evolution, controversies and association with cardiovascular disease risk. Indian J Clin Cardiol. 2020;1(2):77–85. https://doi.org/10.1177/2632463620935030 [34] Brady TM. The role of obesity in the development of left ventricular hypertrophy among children and adolescents. Curr Hypertens Rep. 2016;18(1):3. https://doi.org/10.1007/s11906-015-0608-3.
• [35] Maugeri A, Hruskova J, Jakubik J, Barchitta M, Lo Re O, Kunzova S, Medina-Inojosa JR, Agodi A, Sciacca S, Vinciguerra M. Independent effects of hypertension and obesity on left ventricular mass and geometry: evidence from the cardiovision 2030 study. J Clin Med. 2019;8(3):370. https://doi.org/10.3390/jcm8030370.
• [36] Kong P, Christia P, Frangogiannis NG. The pathogenesis of cardiac fibrosis. Cell Mol Life Sci. 2014;71(4):549-574. https://doi.org/10.1007/s00018-013-1349-6.
• [37] Zhang ZY, Dang SP, Li SS, Liu Y, Qi MM, Wang N, Miao LF, Wu Y, Li XY, Wang CX, Qian LL, Wang RX. glucose fluctuations aggravate myocardial fibrosis via the nuclear factor-κB-mediated nucleotide-binding oligomerization domain-like receptor Protein 3 inflammasome activation. Front Cardiovasc Med. 2022;9:748183. https://doi.org/10.3389/fcvm.2022.748183..
• [38] Biernacka A, Dobaczewski M, Frangogiannis NG. TGF-β signaling in fibrosis. Growth Factors. 2011;29(5):196-202. https://doi.org/10.3109/08977194.2011.595714.
• [39] Dobaczewski M, Chen W, Frangogiannis NG. Transforming growth factor (TGF)-β signaling in cardiac remodeling. J Mol Cell Cardiol. 2011;51(4):600-606. https://doi.org/10.1016/j.yjmcc.2010.10.033.
• [40] Abed HS, Samuel CS, Lau DH, Kelly DJ, Royce SG, Alasady M, Mahajan R, Kuklik P, Zhang Y, Brooks AG, Nelson AJ, Worthley SG, Abhayaratna WP, Kalman JM, Wittert GA, Sanders P. Obesity results in progressive atrial structural and electrical remodeling: implications for atrial fibrillation. Heart Rhythm. 2013;10(1):90-100. https://doi.org/10.1016/j.hrthm.2012.08.043.
• [41] Cavalera M, Wang J, Frangogiannis NG. Obesity, metabolic dysfunction, and cardiac fibrosis: pathophysiological pathways, molecular mechanisms, and therapeutic opportunities. Transl Res. 2014;164(4):323-335. https://doi.org/10.1016/j.trsl.2014.05.001.
• [42] Zhong W, Huan XD, Cao Q, Yang J. Cardioprotective effect of epigallocatechin-3-gallate against myocardial infarction in hypercholesterolemic rats. Exp Ther Med. 2015;9(2):405-410. https://doi.org/10.3892/etm.2014.2135.
• [43] Cui Y, Wang Y, Liu G. Epigallocatechin gallate (EGCG) attenuates myocardial hypertrophy and fibrosis induced by transverse aortic constriction via inhibiting the Akt/mTOR pathway. Pharm Biol. 2021;59(1):1305-1313. https://doi.org/10.1080/13880209.2021.1972124.
• [44] Cai W, Sakaguchi M, Kleinridders A, Gonzalez-Del Pino G, Dreyfuss JM, O'Neill BT, Ramirez AK, Pan H, Winnay JN, Boucher J, Eck MJ, Kahn CR. Domain-dependent effects of insulin and IGF-1 receptors on signalling and gene expression. Nat Commun. 2017;8:14892. https://doi.org/10.1038/ncomms14892.
• [45] Agunloye OM, Oboh G, Ademiluyi AO, Ademosun AO, Akindahunsi AA, Oyagbemi AA, Omobowale TO, Ajibade TO, Adedapo AA. Cardio-protective and antioxidant properties of caffeic acid and chlorogenic acid: Mechanistic role of angiotensin converting enzyme, cholinesterase and arginase activities in cyclosporine induced hypertensive rats. Biomed Pharmacother. 2019;109:450-458. https://doi.org/10.1016/j.biopha.2018.10.044.
• [46] Agunloye OM, Oboh G. High cholesterol diet promotes dysfunction of arginase and cholinergic enzymatic system in rats: ameliorative role of caffeic and chlorogenic acids. J Complement Integr Med. 2020;18(1):67-74. https://doi.org/10.1515/jcim-2019-0271.
• [47] Chomsy IN, Rohman MS, Lukitasari M, Nugroho DA, Khotimah H. Cardiac fibrosis attenuation by chlorogenic acid and epigallocatechin-gallate mediated by suppression of Galectin-3 gene expression and collagen deposition in rat metabolic syndrome model. Indian J Forensic Med Toxicol. 2020;15(2): 2567-2574. https://doi.org/10.37506/ijfmt.v15i2.14759.
• [48] Rohman M, Lukitasari M, Nugroho D, Nashi W, Nugraheini N, Sardjono T. Development of an experimental model of metabolic syndrome in Sprague Dawley rat. Res J Life Sci. 2017;4(1):76-86. https://doi.org/10.21776/ub.rjls.2017.004.01.10.
• [49] Lukitasari M, Nugroho DA, Rohman MS. 28 Green tea extract administration had a beneficial effect on ppar alpha and ppar gamma gene expression in metabolic syndrome rat model. J Hypertens. 2018; 36(9). https://doi.org/10.1097/01.hjh.0000544393.97442.09.
• [50] Liang H, Liang Y, Dong J, Lu J, Xu H, Wang H. Decaffeination of fresh green tea leaf (Camellia sinensis) by hot water treatment. Food Chem. 2007; 101(4): 1451–1456. https://doi.org/10.1016/J.Foodchem.2006.03.054.