Skip to main content

Advertisement

SpringerLink
Log in

Resveratrol prevents pathological but not physiological cardiac hypertrophy

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

The mechanisms responsible for how resveratrol inhibits pathological left ventricular hypertrophy (LVH) but not physiological LVH have not been elucidated. Herein, we show that in rat cardiomyocytes, lower concentrations of resveratrol (0.1 and 1 μM) are efficient at selectively inhibiting important regulators involved in pathological LVH (such as nuclear factor of activated T cells (NFAT)) while not affecting pathways involved in physiological LVH (Akt and p70S6 kinase (p70S6K)). These differential responses are also observed in both mouse and rat models of in vivo physiological and pathological LVH. Interestingly, in all of the experiments involving a low concentration of resveratrol (1 μM), the observed effects on Akt, p70S6K, and NFAT were independent from AMP-activated protein kinase (AMPK) activation while these effects at higher concentrations of resveratrol (50 μM) were potentiated by AMPK activation. In summary, we show that resveratrol can concentration/dose selectively inhibit various pro-hypertrophic signaling pathways and that resveratrol has differential effects on the modification of these signaling cascades in response to pathological stimuli versus physiological stimuli. This has important clinical implications as our findings support the concept that resveratrol may be useful in the selective treatment of pathological LVH.

Key message

  • Resveratrol differentially regulates pathological and physiological cardiac hypertrophy.

  • Resveratrol dose selectively inhibits pathological cardiac signaling pathways.

  • Resveratrol inhibits NFAT-dependent transcription.

  • At low concentrations, effects of resveratrol are AMPK-independent.

  • Resveratrol may be used to selectively treat pathological cardiac hypertrophy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Lorell BH, Carabello BA (2000) Left ventricular hypertrophy: pathogenesis, detection, and prognosis. Circulation 102:470–479

    Article  CAS  PubMed  Google Scholar 

  2. Ellison GM, Waring CD, Vicinanza C, Torella D (2012) Physiological cardiac remodelling in response to endurance exercise training: cellular and molecular mechanisms. Heart 98:5–10

    Article  CAS  PubMed  Google Scholar 

  3. Hannan RD, Jenkins A, Jenkins AK, Brandenburger Y (2003) Cardiac hypertrophy: a matter of translation. Clin Exp Pharmacol Physiol 30:517–527

    Article  CAS  PubMed  Google Scholar 

  4. Dolinsky VW, Dyck JR (2006) Role of AMP-activated protein kinase in healthy and diseased hearts. Am J Physiol Heart Circ Physiol 291:H2557–H2569

    Article  CAS  PubMed  Google Scholar 

  5. Zarrinpashneh E, Beauloye C, Ginion A, Pouleur AC, Havaux X, Hue L, Viollet B, Vanoverschelde JL, Bertrand L (2008) AMPKalpha2 counteracts the development of cardiac hypertrophy induced by isoproterenol. Biochem Biophys Res Commun 376:677–681

    Article  CAS  PubMed  Google Scholar 

  6. Chan AY, Dolinsky VW, Soltys CL, Viollet B, Baksh S, Light PE, Dyck JR (2008) Resveratrol inhibits cardiac hypertrophy via AMP-activated protein kinase and Akt. J Biol Chem 283:24194–24201

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Chan AY, Soltys CL, Young ME, Proud CG, Dyck JR (2004) Activation of AMP-activated protein kinase inhibits protein synthesis associated with hypertrophy in the cardiac myocyte. J Biol Chem 279:32771–32779

    Article  CAS  PubMed  Google Scholar 

  8. Li HL, Yin R, Chen D, Liu D, Wang D, Yang Q, Dong YG (2007) Long-term activation of adenosine monophosphate-activated protein kinase attenuates pressure-overload-induced cardiac hypertrophy. J Cell Biochem 100:1086–1099

    Article  CAS  PubMed  Google Scholar 

  9. Molkentin JD, Lu JR, Antos CL, Markham B, Richardson J, Robbins J, Grant SR, Olson EN (1998) A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 93:215–228

    Article  CAS  PubMed  Google Scholar 

  10. Wilkins BJ, Dai YS, Bueno OF, Parsons SA, Xu J, Plank DM, Jones F, Kimball TR, Molkentin JD (2004) Calcineurin/NFAT coupling participates in pathological, but not physiological, cardiac hypertrophy. Circ Res 94:110–118

    Article  CAS  PubMed  Google Scholar 

  11. Dolinsky VW, Dyck JR (2014) Experimental studies of the molecular pathways regulated by exercise and resveratrol in heart, skeletal muscle and the vasculature. Molecules 19:14919–14947

    Article  PubMed  Google Scholar 

  12. Dolinsky VW, Chan AY, Robillard Frayne I, Light PE, Des Rosiers C, Dyck JR (2009) Resveratrol prevents the prohypertrophic effects of oxidative stress on LKB1. Circulation 119:1643–1652

    Article  CAS  PubMed  Google Scholar 

  13. Juric D, Wojciechowski P, Das DK, Netticadan T (2007) Prevention of concentric hypertrophy and diastolic impairment in aortic-banded rats treated with resveratrol. Am J Physiol Heart Circ Physiol 292:H2138–H2143

    Article  CAS  PubMed  Google Scholar 

  14. Liu Z, Song Y, Zhang X, Liu Z, Zhang W, Mao W, Wang W, Cui W, Zhang X, Jia X et al (2005) Effects of trans-resveratrol on hypertension-induced cardiac hypertrophy using the partially nephrectomized rat model. Clin Exp Pharmacol Physiol 32:1049–1054

    Article  PubMed  Google Scholar 

  15. Rimbaud S, Ruiz M, Piquereau J, Mateo P, Fortin D, Veksler V, Garnier A, Ventura-Clapier R (2011) Resveratrol improves survival, hemodynamics and energetics in a rat model of hypertension leading to heart failure. PLoS One 6:e26391

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Thandapilly SJ, Wojciechowski P, Behbahani J, Louis XL, Yu L, Juric D, Kopilas MA, Anderson HD, Netticadan T (2010) Resveratrol prevents the development of pathological cardiac hypertrophy and contractile dysfunction in the SHR without lowering blood pressure. Am J Hypertens 23:192–196

    Article  CAS  PubMed  Google Scholar 

  17. Toklu HZ, Sehirli O, Ersahin M, Suleymanoglu S, Yiginer O, Emekli-Alturfan E, Yarat A, Yegen BC, Sener G (2010) Resveratrol improves cardiovascular function and reduces oxidative organ damage in the renal, cardiovascular and cerebral tissues of two-kidney, one-clip hypertensive rats. J Pharm Pharmacol 62:1784–1793

    Article  CAS  PubMed  Google Scholar 

  18. Dolinsky VW, Chakrabarti S, Pereira TJ, Oka T, Levasseur J, Beker D, Zordoky BN, Morton JS, Nagendran J, Lopaschuk GD et al (2013) Resveratrol prevents hypertension and cardiac hypertrophy in hypertensive rats and mice. Biochim Biophys Acta 1832:1723–1733

    Article  CAS  PubMed  Google Scholar 

  19. Dolinsky VW, Jones KE, Sidhu RS, Haykowsky M, Czubryt MP, Gordon T, Dyck JR (2012) Improvements in skeletal muscle strength and cardiac function induced by resveratrol contribute to enhanced exercise performance in rats. J Physiol 590:2783–2799

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Dolinsky VW, Rueda-Clausen CF, Morton JS, Davidge ST, Dyck JR (2011) Continued postnatal administration of resveratrol prevents diet-induced metabolic syndrome in rat offspring born growth restricted. Diabetes 60:2274–2284

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Dolinsky VW, Rogan KJ, Sung MM, Zordoky BN, Haykowsky MJ, Young ME, Jones LW, Dyck JR (2013) Both aerobic exercise and resveratrol supplementation attenuate doxorubicin-induced cardiac injury in mice. Am J Physiol Endocrinol Metab 305:E243–E253

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Kovacic S, Soltys CL, Barr AJ, Shiojima I, Walsh K, Dyck JR (2003) Akt activity negatively regulates phosphorylation of AMP-activated protein kinase in the heart. J Biol Chem 278:39422–39427

    Article  CAS  PubMed  Google Scholar 

  23. Mizutani S, Ishii M, Hattori A, Nomura S, Numaguchi Y, Tsujimoto M, Kobayshi H, Murohara T, Wright JW (2008) New insights into the importance of aminopeptidase A in hypertension. Heart Fail Rev 13:273–284

    Article  CAS  PubMed  Google Scholar 

  24. Neri Serneri GG, Boddi M, Modesti PA, Cecioni I, Coppo M, Padeletti L, Michelucci A, Colella A, Galanti G (2001) Increased cardiac sympathetic activity and insulin-like growth factor-I formation are associated with physiological hypertrophy in athletes. Circ Res 89:977–982

    Article  CAS  PubMed  Google Scholar 

  25. Yeh JK, Aloia JF, Chen M, Sprintz S (1994) Effect of growth hormone administration and treadmill exercise on the body composition of rats. J Appl Physiol (1985) 77:23–29

  26. McMullen JR, Jennings GL (2007) Differences between pathological and physiological cardiac hypertrophy: novel therapeutic strategies to treat heart failure. Clin Exp Pharmacol Physiol 34:255–262

    Article  CAS  PubMed  Google Scholar 

  27. Sundaresan NR, Pillai VB, Gupta MP (2011) Emerging roles of SIRT1 deacetylase in regulating cardiomyocyte survival and hypertrophy. J Mol Cell Cardiol 51:614–618

  28. Price NL, Gomes AP, Ling AJ, Duarte FV, Martin-Montalvo A, North BJ, Agarwal B, Ye L, Ramadori G, Teodoro JS et al (2012) SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab 15:675–690

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P et al (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 127:1109–1122

    Article  CAS  PubMed  Google Scholar 

  30. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K et al (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444:337–342

    Article  CAS  PubMed  Google Scholar 

  31. Patel KR, Andreadi C, Britton RG, Horner-Glister E, Karmokar A, Sale S, Brown VA, Brenner DE, Singh R, Steward WP et al (2013) Sulfate metabolites provide an intracellular pool for resveratrol generation and induce autophagy with senescence. Sci Transl Med 5:205ra133

    Article  PubMed  Google Scholar 

  32. Wojciechowski P, Juric D, Louis XL, Thandapilly SJ, Yu L, Taylor C, Netticadan T (2010) Resveratrol arrests and regresses the development of pressure overload- but not volume overload-induced cardiac hypertrophy in rats. J Nutr 140:962–968

    Article  CAS  PubMed  Google Scholar 

  33. Chan V, Fenning A, Iyer A, Hoey A, Brown L (2011) Resveratrol improves cardiovascular function in DOCA-salt hypertensive rats. Curr Pharm Biotechnol 12:429–436

    Article  CAS  PubMed  Google Scholar 

  34. Um JH, Park SJ, Kang H, Yang S, Foretz M, McBurney MW, Kim MK, Viollet B, Chung JH (2010) AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol. Diabetes 59:554–563

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors acknowledge the excellent technical assistance of Jamie Boisvenuee, Amy Barr, Jody Levasseur, and Yang Zhao of the University of Alberta. This research was supported by grants from the Canadian Institutes of Health Research (CIHR) to JRBD. VWD is the Dr. J.A. Moorhouse fellow of the Diabetes Foundation of Manitoba. AYMC was a holder of a HSFC Doctoral Research Award and an AHFMR MD/PhD Studentship Award.

Conflict of interest

There are no conflicts of interest.

Author information

Authors and Affiliations

  1. Cardiovascular Research Centre, Faculty of Medicine and Dentistry, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB, Canada

    Vernon W. Dolinsky, Carrie-Lynn M. Soltys, Kyle J. Rogan, Anita Y. M. Chan, Jeevan Nagendran & Jason R. B. Dyck

  2. Division of Cardiac Surgery, Faculty of Medicine and Dentistry, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB, Canada

    Shaohua Wang

  3. Department of Pharmacology and Therapeutics, Manitoba Institute of Child Health, University of Manitoba, Winnipeg, MB, Canada

    Vernon W. Dolinsky

  4. 458 Heritage Medical Research Centre, University of Alberta, Edmonton, AB, T6G 2S2, Canada

    Jason R. B. Dyck

Authors
  1. Vernon W. Dolinsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carrie-Lynn M. Soltys
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kyle J. Rogan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anita Y. M. Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jeevan Nagendran
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shaohua Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jason R. B. Dyck
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jason R. B. Dyck.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOC 728 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dolinsky, V.W., Soltys, CL.M., Rogan, K.J. et al. Resveratrol prevents pathological but not physiological cardiac hypertrophy. J Mol Med 93, 413–425 (2015). https://doi.org/10.1007/s00109-014-1220-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-014-1220-8

Keywords

Search

Navigation