[6]-Gingerol: A Novel AT₁ Antagonist for the Treatment of Cardiovascular Disease

Abstract

Considering the prevalence of cardiovascular disease in public health and the limited validated therapeutic options, this study aimed to find novel compounds targeting the angiotensin II type 1 receptor, accepted as a therapeutic target in cardiovascular disease. A small library consisting of 89 compounds from 39 Chinese herbs was profiled using a cell-based calcium mobilization assay which was developed and characterized for high-throughput screening. [6]-Gingerol derived from Zingiber officinale Roscoe (ginger) was identified as a novel angiotensin II type 1 receptor antagonist, with an IC₅₀ value of 8.173 µM. The hit was further tested by a specificity assay indicating that it had no antagonistic effects on other evaluated GPCRs, such as endothelin receptors. The major ingredient of ginger, [6]-gingerol, could inhibit angiotensin II type 1 receptor activation, which partially clarified the mechanism of ginger regulating blood pressure and strengthening heart in the cardiovascular system.

Key words

[6]-gingerol - AT₁ antagonist - calcium assay - high-throughput screening - cardiovascular disease - Chinese herb

• References

• 1 Karamitsos TD, Francis JM, Myerson S, Selvanayagam JB, Neubauer S. The role of cardiovascular magnetic resonance imaging in heart failure. J Am Coll Cardiol 2009; 54: 1407-1424
• 2 Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, Ferguson TB, Fold E, Furie K, Gillespie C, Go A, Greenlund K, Haase N, Hailpern S, Ho PM, Howard V, Kissela B, Kittner S, Lackland D, Lisabeth L, Marelli A, McDermott MM, Meigs J, Mozaffarian D, Mussolino M, Nichol G, Roger VL, Rosamond W, Sacco R, Sorlie P, Stafford R, Thom T, Wasserthiel-Smoller S, Wong ND, Wylie-Rosett J. Heart disease and stroke statistics–2010 update: a report from the American Heart Association. Circulation 2010; 121: e46-e215
• 3 Leal J, Luengo-Fernandez R, Gray A, Petersen S, Rayner M. Economic burden of cardiovascular diseases in the enlarged European Union. Eur Heart J 2006; 27: 1610-1619
• 4 de Bekker-Grob EW, van Dulmen S, van den Berg M, Verheij RA, Slobbe LC. Primary prevention of cardiovascular diseases: a cost study in family practices. BMC Fam Pract 2011; 12: 69
• 5 Drewnowski A, Popkin BM. The nutrition transition: new trends in the global diet. Nutr Rev 1997; 55: 31-43
• 6 Paeratakul S, Popkin BM, Keyou G, Adair LS, Stevens J. Changes in diet and physical activity affect the body mass index of Chinese adults. Int J Obes Relat Metab Disord 1998; 22: 424-431
• 7 Wildman RP, Gu D, Muntner P, Wu X, Reynolds K, Duan X, Chen CS, Huang G, Bazzano LA, He J. Trends in overweight and obesity in Chinese adults: between 1991 and 1999–2000. Obesity (Silver Spring) 2008; 16: 1448-1453
• 8 de Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T. International Union of Pharmacology. XXIII. The Angiotensin II Receptors. Pharmacol Rev 2000; 52: 415-472
• 9 Timmermans PB. Pharmacological properties of angiotensin II receptor antagonists. Can J Cardiol 1999; 15 (Suppl. F) 26F-28F
• 10 Norris K, Vaughn C. The role of renin-angiotensin-aldosterone system inhibition in chronic kidney disease. Expert Rev Cardiovasc Ther 2003; 1: 51-63
• 11 Manohar P, Pina IL. Therapeutic role of angiotensin II receptor blockers in the treatment of heart failure. Mayo Clin Proc 2003; 78: 334-338
• 12 Liu Y, Yin HJ, Shi DZ, Chen KJ. Chinese herb and formulas for promoting blood circulation and removing blood stasis and antiplatelet therapies. Evid Based Complement Alternat Med 2012; 2012: 184503
• 13 Valli G, Giardina EG. Benefits, adverse effects and drug interactions of herbal therapies with cardiovascular effects. J Am Coll Cardiol 2002; 39: 1083-1095
• 14 Ling S, Dai A, Guo Z, Yan X, Komesaroff PA. Effects of a Chinese herbal preparation on vascular cells in culture: mechanisms of cardiovascular protection. Clin Exp Pharmacol Physiol 2005; 32: 571-578
• 15 Gao D, Song J, Hu J, Lin J, Zheng L, Cai J, Du J, Chen K. Angiogenesis promoting effects of Chinese herbal medicine for activating blood circulation to remove stasis on chick embryo chorio-allantoic membrane. Zhongguo Zhong Xi Yi Jie He Za Zhi 2005; 25: 912-915
• 16 Zhang DW, Liu JG, Feng JT, Zhang L, Yang XP, Shi DZ, Liang XM. Effects of effective components compatibility of aqueous extracts of Salviae Miltiorrhizae and Rhizoma Chuanxiong on rat myocardial ischemia/reperfusion injury. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2010; 22: 109-112
• 17 Vanderheyden PM, Fierens FL, De Backer JP, Fraeyman N, Vauquelin G. Distinction between surmountable and insurmountable selective AT1 receptor antagonists by use of CHO-K1 cells expressing human angiotensin II AT1 receptors. Br J Pharmacol 1999; 126: 1057-1065
• 18 Maillard MP, Perregaux C, Centeno C, Stangier J, Wienen W, Brunner HR, Burnier M. In vitro and in vivo characterization of the activity of telmisartan: an insurmountable angiotensin II receptor antagonist. J Pharmacol Exp Ther 2002; 302: 1089-1095
• 19 Zhang JH, Chung TD, Oldenburg KR. A simple statistical parameter for use in evaluation and validation of high throughput screening assays. J Biomol Screen 1999; 4: 67-73
• 20 Moller HJ, Volz HP, Reimann IW, Stoll KD. Opipramol for the treatment of generalized anxiety disorder: a placebo-controlled trial including an alprazolam-treated group. J Clin Psychopharmacol 2001; 21: 59-65
• 21 Dedov VN, Tran VH, Duke CC, Connor M, Christie MJ, Mandadi S, Roufogalis BD. Gingerols: a novel class of vanilloid receptor (VR1) agonists. Br J Pharmacol 2002; 137: 793-798
• 22 Clapham DE. TRP channels as cellular sensors. Nature 2003; 426: 517-524
• 23 Wang DH. Transient receptor potential vanilloid channels in hypertension, inflammation, and end organ damage: an imminent target of therapy for cardiovascular disease?. Curr Opin Cardiol 2008; 23: 356-363
• 24 Shoji N, Iwasa A, Takemoto T, Ishida Y, Ohizumi Y. Cardiotonic principles of ginger (Zingiber officinale Roscoe). J Pharm Sci 1982; 71: 1174-1175
• 25 Vasanthi HR, Parameswari RP. Indian spices for healthy heart – an overview. Curr Cardiol Rev 2010; 6: 274-279
• 26 Zick SM, Ruffin MT, Djuric Z, Normolle D, Brenner DE. Quantitation of 6-, 8- and 10-Gingerols and 6-Shogaol in Human Plasma by High-Performance Liquid Chromatography with Electrochemical Detection. Int J Biomed Sci 2010; 6: 233-240
• 27 Carey RM, Siragy HM. Newly recognized components of the renin-angiotensin system: potential roles in cardiovascular and renal regulation. Endocr Rev 2003; 24: 261-271
• 28 Stanton A. Therapeutic potential of renin inhibitors in the management of cardiovascular disorders. Am J Cardiovasc Drugs 2003; 3: 389-394
• 29 Mehta PK, Griendling KK. Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol 2007; 292: C82-C97