Kaempferol Attenuates Cardiac Hypertrophy via Regulation of ASK1/MAPK Signaling Pathway and Oxidative Stress

Abstract

Kaempferol has been demonstrated to provide benefits for the treatment of atherosclerosis, coronary heart disease, hyperlipidemia, and diabetes through its antioxidant and anti-inflammatory properties. However, its role in cardiac hypertrophy remains to be elucidated. The aim of our study was to investigate the effects of kaempferol on cardiac hypertrophy and the underlying mechanism. Mice subjected to aorta banding were treated with or without kaempferol (100 mg/kg/d, p. o.) for 6 weeks. Echocardiography was performed to evaluate cardiac function. Mice hearts were collected for pathological observation and molecular mechanism investigation. H9c2 cardiomyocytes were stimulated with or without phenylephrine for in vitro study. Kaempferol significantly attenuated cardiac hypertrophy induced by aorta banding as evidenced by decreased cardiomyocyte areas and interstitial fibrosis, accompanied with improved cardiac functions and decreased apoptosis. The ASK1/MAPK signaling pathways (JNK1/2 and p38) were markedly activated in the aorta banding mouse heart but inhibited by kaempferol treatment. In in vitro experiments, kaempferol also inhibited the activity of ASK1/JNK1/2/p38 signaling pathway and the enlargement of H9c2 cardiomyocytes. Furthermore, our study revealed that kaempferol could protect the mouse heart and H9c2 cells from pathological oxidative stress. Our investigation indicated that treatment with kaempferol protects against cardiac hypertrophy, and its cardioprotection may be partially explained by the inhibition of the ASK1/MAPK signaling pathway and the regulation of oxidative stress.

Key words

kaempferol - cardiac hypertrophy - MAPK - ASK1 - oxidative stress

^* Hong Feng and Jianlei Cao contributed equally to this work.

• References

• 1 Ziaeian B, Fonarow GC. Epidemiology and aetiology of heart failure. Nat Rev Cardiol 2016; 13: 368-378
• 2 Ezekowitz JA, Kaul P, Bakal JA, Quan H, McAlister FA. Trends in heart failure care: has the incident diagnosis of heart failure shifted from the hospital to the emergency department and outpatient clinics?. Eur J Heart Fail 2011; 13: 142-147
• 3 Schiattarella GG, Hill JA. Inhibition of hypertrophy is a good therapeutic strategy in ventricular pressure overload. Circulation 2015; 131: 1435-1447
• 4 Rose BA, Force T, Wang Y. Mitogen-activated protein kinase signaling in the heart: angels versus demons in a heart-breaking tale. Physiol Rev 2010; 90: 1507-1546
• 5 Ravingerova T, Barancik M, Strniskova M. Mitogen-activated protein kinases: a new therapeutic target in cardiac pathology. Mol Cell Biochem 2003; 247: 127-138
• 6 Calderon-Montano JM, Burgos-Moron E, Perez-Guerrero C, Lopez-Lazaro M. A review on the dietary flavonoid kaempferol. Mini Rev Med Chem 2011; 11: 298-344
• 7 Lin J, Rexrode KM, Hu F, Albert CM, Chae CU, Rimm EB, Stampfer MJ, Manson JE. Dietary intakes of flavonols and flavones and coronary heart disease in us women. Am J Epidemiol 2007; 165: 1305-1313
• 8 Zhou M, Ren H, Han J, Wang W, Zheng Q, Wang D. Protective effects of kaempferol against myocardial ischemia/reperfusion injury in isolated rat heart via antioxidant activity and inhibition of glycogen synthase kinase-3beta. Oxid Med Cell Longev 2015; 2015: 481405
• 9 Suchal K, Malik S, Gamad N, Malhotra RK, Goyal SN, Chaudhary U, Bhatia J, Ojha S, Arya DS. Kaempferol attenuates myocardial ischemic injury via inhibition of MAPK signaling pathway in experimental model of myocardial ischemia-reperfusion injury. Oxid Med Cell Longev 2016; 2016: 7580731
• 10 Klawitter J, Agardi E, Corby K, Leibfritz D, Lowes BD, Christians U, Seres T. Association of dj-1/pten/akt- and ask1/p 38-mediated cell signalling with ischaemic cardiomyopathy. Cardiovasc Res 2013; 97: 66-76
• 11 Bell RM, Botker HE, Carr RD, Davidson SM, Downey JM, Dutka DP, Heusch G, Ibanez B, Macallister R, Stoppe C, Ovize M, Redington A, Walker JM, Yellon DM. 9th Hatter Biannual Meeting: position document on ischaemia/reperfusion injury, conditioning and the ten commandments of cardioprotection. Basic Res Cardiol 2016; 111: 41
• 12 Liu Q, Sargent MA, York AJ, Molkentin JD. Ask1 regulates cardiomyocyte death but not hypertrophy in transgenic mice. Circ Res 2009; 105: 1110-1117
• 13 Zhang Y, Liu Y, Zhu XH, Zhang XD, Jiang DS, Bian ZY, Zhang XF, Chen K, Wei X, Gao L, Zhu LH, Yang Q, Fan GC, Lau WB, Ma X, Li H. Dickkopf-3 attenuates pressure overload-induced cardiac remodelling. Cardiovasc Res 2014; 102: 35-45
• 14 Yamaguchi O, Higuchi Y, Hirotani S, Kashiwase K, Nakayama H, Hikoso S, Takeda T, Watanabe T, Asahi M, Taniike M, Matsumura Y, Tsujimoto I, Hongo K, Kusakari Y, Kurihara S, Nishida K, Ichijo H, Hori M, Otsu K. Targeted deletion of apoptosis signal-regulating kinase 1 attenuates left ventricular remodeling. Proc Natl Acad Sci U S A 2003; 100: 15883-15888
• 15 Nakamura T, Kataoka K, Fukuda M, Nako H, Tokutomi Y, Dong YF, Ichijo H, Ogawa H, Kim-Mitsuyama S. Critical role of apoptosis signal-regulating kinase 1 in aldosterone/salt-induced cardiac inflammation and fibrosis. Hypertension 2009; 54: 544-551
• 16 Hikoso S, Ikeda Y, Yamaguchi O, Takeda T, Higuchi Y, Hirotani S, Kashiwase K, Yamada M, Asahi M, Matsumura Y, Nishida K, Matsuzaki M, Hori M, Otsu K. Progression of heart failure was suppressed by inhibition of apoptosis signal-regulating kinase 1 via transcoronary gene transfer. J Am Coll Cardiol 2007; 50: 453-462
• 17 Bondonno CP, Croft KD, Ward N, Considine MJ, Hodgson JM. Dietary flavonoids and nitrate: effects on nitric oxide and vascular function. Nutr Rev 2015; 73: 216-235
• 18 Wray DW, Amann M, Richardson RS. Peripheral vascular function, oxygen delivery and utilization: the impact of oxidative stress in aging and heart failure with reduced ejection fraction. Heart Fail Rev 2016;
• 19 Tham YK, Bernardo BC, Ooi JY, Weeks KL, McMullen JR. Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets. Arch Toxicol 2015; 89: 1401-1438
• 20 Huang Q, Zhou HJ, Zhang H, Huang Y, Hinojosa-Kirschenbaum F, Fan P, Yao L, Belardinelli L, Tellides G, Giordano FJ, Budas GR, Min W. Thioredoxin-2 inhibits mitochondrial reactive oxygen species generation and apoptosis stress kinase-1 activity to maintain cardiac function. Circulation 2015; 131: 1082-1097
• 21 Lu J, Holmgren A. Thioredoxin system in cell death progression. Antioxid Redox Signal 2012; 17: 1738-1747
• 22 Jain AK, Mehra NK, Swarnakar NK. Role of Antioxidants for the Treatment of Cardiovascular Diseases: Challenges and Opportunities. Curr Pharm Des 2015; 21: 4441-4455
• 23 Travers JG, Kamal FA, Robbins J, Yutzey KE, Blaxall BC. Cardiac Fibrosis: The Fibroblast Awakens. Circ Res 2016; 118: 1021-1040
• 24 Lighthouse JK, Small EM. Transcriptional control of cardiac fibroblast plasticity. J Mol Cell Cardiol 2016; 91: 52-60
• 25 Hill KS, Erdogan E, Khoor A, Walsh MP, Leitges M, Murray NR, Fields AP. Protein kinase Cα suppresses Kras-mediated lung tumor formation through activation of a p 38 MAPK-TGFβ signaling axis. Oncogene 2014; 33: 2134-2144
• 26 Watkins SJ, Jonker L, Arthur HM. A direct interaction between TGFbeta activated kinase 1 and the TGFbeta type II receptor: implications for TGFbeta signalling and cardiac hypertrophy. Cardiovasc Res 2006; 69: 432-439
• 27 Chen Z, Zheng S, Li L, Jiang H. Metabolism of flavonoids in human: A comprehensive review. Curr Drug Metab 2014; 15: 48-61
• 28 Zheng L, Zhu L, Zhao M, Shi J, Li Y, Yu J, Jiang H, Wu J, Tong Y, Liu Y, Hu M, Lu L, Liu Z. In Vivo Exposure of Kaempferol is Driven by Phase II Metabolic Enzymes and Efflux Transporters. AAPS J 2016; 18: 1289-1299
• 29 DuPont MS, Day AJ, Bennett RN, Mellon FA, Kroon PA. Absorption of kaempferol from endive, a source of kaempferol-3-glucuronide, in humans. Eur J Clin Nutr 2004; 58: 947-954
• 30 Hertog MG, Feskens EJ, Hollman PC, Katan MB, Kromhout D. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet 1993; 342: 1007-1011
• 31 Geleijnse JM, Launer LJ, Van der Kuip DA, Hofman A, Witteman JC. Inverse association of tea and flavonoid intakes with incident myocardial infarction: the Rotterdam Study. Am J Clin Nutr 2002; 75: 880-886
• 32 Al-Numair KS, Veeramani C, Alsaif MA, Chandramohan G. Influence of kaempferol, a flavonoid compound, on membrane-bound ATPases in streptozotocin-induced diabetic rats. Pharm Biol 2015; 53: 1372-1378
• 33 Hoang MH, Jia Y, Mok B, Jun HJ, Hwang KY, Lee SJ. Kaempferol ameliorates symptoms of metabolic syndrome by regulating activities of liver x receptor-beta. J Nutr Biochem 2015; 26: 868-875
• 34 Marano G, Ferrari AU. Surgical animal model of ventricular hypertrophy. Methods Mol Med 2007; 139: 95-104