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Journal of Molecular Histology

, Volume 44, Issue 5, pp 575–585 | Cite as

Hesperetin protects against cardiac remodelling induced by pressure overload in mice

  • Wei Deng
  • Duan Jiang
  • Yi Fang
  • Heng Zhou
  • Zhihong Cheng
  • Yafen Lin
  • Rui Zhang
  • Jieyu Zhang
  • Peng Pu
  • Yuan Liu
  • Zhouyan Bian
  • Qizhu Tang
Original Paper

Abstract

Cardiac remodelling is a major determinant of heart failure (HF) and is characterised by cardiac hypertrophy, fibrosis, oxidative stress and myocytes apoptosis. Hesperetin, which belongs to the flavonoid subgroup of citrus flavonoids, is the main flavonoid in oranges and possesses multiple pharmacological properties. However, its role in cardiac remodelling remains unknown. We determined the effect of hesperetin on cardiac hypertrophy, fibrosis and heart function using an aortic banding (AB) mouse. Male, 8–10-week-old, wild-type C57 mice with or without oral hesperetin administration were subjected to AB or a sham operation. Our data demonstrated that hesperetin protected against cardiac hypertrophy, fibrosis and dysfunction induced by AB, as assessed by heart weigh/body weight, lung weight/body weight, heart weight/tibia length, echocardiographic and haemodynamic parameters, histological analysis, and gene expression of hypertrophic and fibrotic markers. Also, hesperetin attenuated oxidative stress and myocytes apoptosis induced by AB. The inhibitory effect of hesperetin on cardiac remodelling was mediated by blocking PKCα/βII-AKT, JNK and TGFβ1-Smad signalling pathways. In conclusion, we found that the orange flavonoid hesperetin protected against cardiac remodelling induced by pressure overload via inhibiting cardiac hypertrophy, fibrosis, oxidative stress and myocytes apoptosis. These findings suggest a potential therapeutic drug for cardiac remodelling and HF.

Keywords

Hesperetin Cardiac remodelling Heart failure 

Notes

Acknowledgments

This work was supported by the National Nature Science Foundation of China [81270303]; and the Fundamental Research Funds for the Central Universities of China [20103020201000193].

Conflict of interest

The authors have no any potential conflicts of interest.

References

  1. Antos CL, McKinsey TA, Frey N et al (2002) Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivo. Proc Natl Acad Sci USA 99:907–912PubMedCrossRefGoogle Scholar
  2. Barry SP, Townsend PA (2010) What causes a broken heart–molecular insights into heart failure. Int Rev Cell Mol Biol 284:113–179PubMedCrossRefGoogle Scholar
  3. Berk BC, Fujiwara K, Lehoux S (2007) ECM remodeling in hypertensive heart disease. J Clin Invest 117:568–575PubMedCrossRefGoogle Scholar
  4. Bernardo BC, Weeks KL, Pretorius L, McMullen JR (2010) Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies. Pharmacol Ther 128:191–227PubMedCrossRefGoogle Scholar
  5. Bisping E, Ikeda S, Kong SW et al (2006) Gata4 is required for maintenance of postnatal cardiac function and protection from pressure overload-induced heart failure. Proc Natl Acad Sci USA 103:14471–14476PubMedCrossRefGoogle Scholar
  6. Burgoyne JR, Mongue-Din H, Eaton P, Shah AM (2012) Redox signaling in cardiac physiology and pathology. Circ Res 111:1091–1106PubMedCrossRefGoogle Scholar
  7. Chaanine AH, Jeong D, Liang L et al (2012) JNK modulates FOXO3a for the expression of the mitochondrial death and mitophagy marker BNIP3 in pathological hypertrophy and in heart failure. Cell Death Dis 3:265PubMedCrossRefGoogle Scholar
  8. DeBosch B, Sambandam N, Weinheimer C, Courtois M, Muslin AJ (2006) Akt2 regulates cardiac metabolism and cardiomyocyte survival. J Biol Chem 281:32841–32851PubMedCrossRefGoogle Scholar
  9. Deng W, Zong J, Bian Z et al (2013) Indole-3-carbinol protects against pressure overload induced cardiac remodeling via activating AMPK-alpha. Mol Nutr Food Res. doi: 10.1002/mnfr.201300012 Google Scholar
  10. Fan GC, Yuan Q, Song G et al (2006) Small heat-shock protein Hsp20 attenuates beta-agonist-mediated cardiac remodeling through apoptosis signal-regulating kinase 1. Circ Res 99:1233–1242PubMedCrossRefGoogle Scholar
  11. Fan X, Turdi S, Ford SP et al (2011) Influence of gestational overfeeding on cardiac morphometry and hypertrophic protein markers in fetal sheep. J Nutr Biochem 22:30–37PubMedCrossRefGoogle Scholar
  12. Houser SR, Margulies KB, Murphy AM et al (2012) Animal models of heart failure: a scientific statement from the American Heart Association. Circ Res 111:131–150PubMedCrossRefGoogle Scholar
  13. Keranen LM, Dutil EM, Newton AC (1995) Protein kinase C is regulated in vivo by three functionally distinct phosphorylations. Curr Biol 5:1394–1403PubMedCrossRefGoogle Scholar
  14. Kim JY, Jung KJ, Choi JS, Chung HY (2006a) Modulation of the age-related nuclear factor-kappaB (NF-kappaB) pathway by hesperetin. Aging Cell 5:401–411PubMedCrossRefGoogle Scholar
  15. Kim JY, Jung KJ, Choi JS, Chung HY (2006b) Modulation of the age-related nuclear factor-kappaB (NF-kappaB) pathway by hesperetin. Aging Cell 5:401–411PubMedCrossRefGoogle Scholar
  16. Li HL, Wang AB, Huang Y et al (2005) Isorhapontigenin, a new resveratrol analog, attenuates cardiac hypertrophy via blocking signaling transduction pathways. Free Radic Biol Med 38:243–257PubMedCrossRefGoogle Scholar
  17. Li P, Wang D, Lucas J et al (2008) Atrial natriuretic peptide inhibits transforming growth factor beta-induced Smad signaling and myofibroblast transformation in mouse cardiac fibroblasts. Circ Res 102:185–192PubMedCrossRefGoogle Scholar
  18. Liang Q, Molkentin JD (2003) Redefining the roles of p38 and JNK signaling in cardiac hypertrophy: dichotomy between cultured myocytes and animal models. J Mol Cell Cardiol 35:1385–1394PubMedCrossRefGoogle Scholar
  19. McMullen JR, Sherwood MC, Tarnavski O et al (2004) Inhibition of mTOR signaling with rapamycin regresses established cardiac hypertrophy induced by pressure overload. Circulation 109:3050–3055PubMedCrossRefGoogle Scholar
  20. Morin B, Nichols LA, Zalasky KM, Davis JW, Manthey JA, Holland LJ (2008) The citrus flavonoids hesperetin and nobiletin differentially regulate low density lipoprotein receptor gene transcription in HepG2 liver cells. J Nutr 138:1274–1281PubMedGoogle Scholar
  21. Ni YG, Berenji K, Wang N et al (2006) Foxo transcription factors blunt cardiac hypertrophy by inhibiting calcineurin signaling. Circulation 114:1159–1168PubMedCrossRefGoogle Scholar
  22. Octavia Y, Brunner-La RHP, Moens AL (2012) NADPH oxidase-dependent oxidative stress in the failing heart: from pathogenic roles to therapeutic approach. Free Radic Biol Med 52:291–297PubMedCrossRefGoogle Scholar
  23. Palfi A, Toth A, Hanto K et al (2006) PARP inhibition prevents postinfarction myocardial remodeling and heart failure via the protein kinase C/glycogen synthase kinase-3beta pathway. J Mol Cell Cardiol 41:149–159PubMedCrossRefGoogle Scholar
  24. Pari L, Shagirtha K (2012) Hesperetin protects against oxidative stress related hepatic dysfunction by cadmium in rats. Exp Toxicol Pathol 64:513–520PubMedCrossRefGoogle Scholar
  25. Sabri A, Steinberg SF (2003) Protein kinase C isoform-selective signals that lead to cardiac hypertrophy and the progression of heart failure. Mol Cell Biochem 251:97–101PubMedCrossRefGoogle Scholar
  26. Scholz EP, Zitron E, Kiesecker C et al (2007) Orange flavonoid hesperetin modulates cardiac hERG potassium channel via binding to amino acid F656. Nutr Metab Cardiovasc Dis 17:666–675PubMedCrossRefGoogle Scholar
  27. Shah AM, Mann DL (2011) In search of new therapeutic targets and strategies for heart failure: recent advances in basic science. Lancet 378:704–712PubMedCrossRefGoogle Scholar
  28. Shih CH, Lin LH, Hsu HT et al (2012) Hesperetin, a selective phosphodiesterase 4 inhibitor, effectively suppresses ovalbumin-induced airway hyperresponsiveness without influencing xylazine/ketamine-induced anesthesia. Evid Based Complement Alternat Med 2012:472897PubMedGoogle Scholar
  29. Singh SS, Kang PM (2011) Mechanisms and inhibitors of apoptosis in cardiovascular diseases. Curr Pharm Des 17:1783–1793PubMedCrossRefGoogle Scholar
  30. Skurk C, Izumiya Y, Maatz H et al (2005) The FOXO3a transcription factor regulates cardiac myocyte size downstream of AKT signaling. J Biol Chem 280:20814–20823PubMedCrossRefGoogle Scholar
  31. Soesanto W, Lin HY, Hu E et al (2009) Mammalian target of rapamycin is a critical regulator of cardiac hypertrophy in spontaneously hypertensive rats. Hypertension 54:1321–1327PubMedCrossRefGoogle Scholar
  32. Trivedi PP, Kushwaha S, Tripathi DN, Jena GB (2011) Cardioprotective effects of hesperetin against doxorubicin-induced oxidative stress and DNA damage in rat. Cardiovasc Toxicol 11:215–225PubMedCrossRefGoogle Scholar
  33. Wang N, Guan P, Zhang JP et al (2011) Fasudil hydrochloride hydrate, a Rho-kinase inhibitor, suppresses isoproterenol-induced heart failure in rats via JNK and ERK1/2 pathways. J Cell Biochem 112:1920–1929PubMedCrossRefGoogle Scholar
  34. Wong WW, Puthalakath H (2008) Bcl-2 family proteins: the sentinels of the mitochondrial apoptosis pathway. IUBMB Life 60:390–397PubMedCrossRefGoogle Scholar
  35. Yan L, Huang H, Tang QZ et al (2010) Breviscapine protects against cardiac hypertrophy through blocking PKC-alpha-dependent signaling. J Cell Biochem 109:1158–1171PubMedGoogle Scholar
  36. Yang HL, Chen SC, Senthil KKJ et al (2012) Antioxidant and anti-inflammatory potential of hesperetin metabolites obtained from hesperetin-administered rat serum: an ex vivo approach. J Agric Food Chem 60:522–532PubMedCrossRefGoogle Scholar
  37. Ye L, Chan FL, Chen S, Leung LK (2012) The citrus flavonone hesperetin inhibits growth of aromatase-expressing MCF-7 tumor in ovariectomized athymic mice. J Nutr Biochem 23:1230–1237PubMedCrossRefGoogle Scholar
  38. Yoshida H, Takamura N, Shuto T et al (2010) The citrus flavonoids hesperetin and naringenin block the lipolytic actions of TNF-alpha in mouse adipocytes. Biochem Biophys Res Commun 394:728–732PubMedCrossRefGoogle Scholar
  39. Zong J, Deng W, Zhou H et al (2013) 3,3′-Diindolylmethane Protects against Cardiac Hypertrophy via 5′-Adenosine Monophosphate-Activated Protein Kinase-alpha2. PLoS One 8:e53427PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Wei Deng
    • 1
    • 2
  • Duan Jiang
    • 1
    • 2
  • Yi Fang
    • 1
    • 2
  • Heng Zhou
    • 1
    • 2
  • Zhihong Cheng
    • 3
  • Yafen Lin
    • 1
    • 2
  • Rui Zhang
    • 1
    • 2
  • Jieyu Zhang
    • 1
    • 2
  • Peng Pu
    • 1
    • 2
  • Yuan Liu
    • 1
    • 2
  • Zhouyan Bian
    • 1
    • 2
  • Qizhu Tang
    • 1
    • 2
  1. 1.Department of CardiologyRenmin Hospital of Wuhan UniversityWuhanPeople’s Republic of China
  2. 2.Cardiovascular Research Institute of Wuhan UniversityWuhanPeople’s Republic of China
  3. 3.National Pharmaceutical Engineering Research CenterShanghaiPeople’s Republic of China

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