Advertisement

Cardiovascular Drugs and Therapy

, Volume 27, Issue 1, pp 5–16 | Cite as

Chronic Metformin Associated Cardioprotection Against Infarction: Not Just a Glucose Lowering Phenomenon

  • Hannah J. Whittington
  • Andrew R. Hall
  • Catarina P. McLaughlin
  • Derek J. Hausenloy
  • Derek M. Yellon
  • Mihaela M. Mocanu
ORIGINAL ARTICLE
First Online:

Abstract

Purpose

Clinical and experimental investigations demonstrated that metformin, a widely used anti-diabetic drug, exhibits cardioprotective properties against myocardial infarction. Interestingly, metformin was previously shown to increase the expression of PGC-1α a key controller of energy metabolism in skeletal muscle, which is down-regulated in diabetic conditions. We hypothesized that chronic treatment with metformin could protect the aged, diabetic heart against ischemia-reperfusion injury (IRI) by up-regulating PGC-1α and improving the impaired functionality of diabetic mitochondria.

Methods

Following 4 weeks of metformin (300 mg/kg) administered in the drinking water, 12 month-old diabetic Goto Kakizaki and non-diabetic Wistar rat hearts were assigned for infarct measurement following 35 min ischemia and 60 min reperfusion or for electron microscopy (EM) and Western blotting (WB) investigations.

Results

Metformin elicited a cardioprotective effect in both non-diabetic and diabetic hearts. In contrast with the diabetic non-treated hearts, the diabetic hearts treated with metformin showed more organized and elongated mitochondria and demonstrated a significant increase in phosphorylated AMPK and in PGC-1α expression.

Conclusions

In summary these results show for the first time that chronic metformin treatment augments myocardial resistance to ischemia-reperfusion injury, by an alternative mechanism in addition to the lowering of blood glucose. This consisted of a positive effect on mitochondrial structure possibly via a pathway involving AMPK activation and PGC-1α. Thus, metformin prescribed chronically to patients may lead to a basal state of cardioprotection thereby potentially limiting the occurrence of myocardial damage by cardiovascular events.

Keywords

Ischemia–reperfusion injury Cardioprotection PGC-1α Metformin 
This is a preview of subscription content, log in to check access.

Notes

Acknowledgments

The authors thank the British Heart Foundation (Program Grant RG/08/015/26411 and FS/09/058/27987) for on-going funding and support. This work was undertaken at University College London Hospital/University College London (UCLH/UCL) which received a proportion of funding from the Department of Health’s National Institute of Health Research (NIHR) Biomedical Research Centres funding scheme.

H.J.W researched data, performed experiments, wrote, reviewed and edited manuscript. A.R.H assisted in experimental work and contributed to discussion. C.P.M. researched data and assisted in experimental work. D.J.H. contributed to discussion. D.M.Y contributed to discussion and reviewed & edited the manuscript. M.M.M researched data, contributed to discussion, reviewed, and edited the manuscript.

The authors thank Louise Casson and other staff at the central unit of Biological Services Unit, UCL, London for the help in maintaining the animal colonies, administrating the drug and blood testing. We also thank Mark Turmaine for assisting with the Electron Microscopy analysis.

Conflict of interest

None declared.

References

  1. 1.
    Turner RC, Millns H, Neil HA, Stratton IM, Manley SE, Matthews DR, Holman RR. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ. 1998;316:823–8.PubMedCrossRefGoogle Scholar
  2. 2.
    Singh M, Arora R, Kodumuri V, Khosla S, Jawad E. Coronary revascularization in diabetic patients: current state of evidence. Exp Clin Cardiol. 2011;16:16–22.PubMedCrossRefGoogle Scholar
  3. 3.
    Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339:229–34.PubMedCrossRefGoogle Scholar
  4. 4.
    Monteiro P, Goncalves L, Providencia LA. Diabetes and cardiovascular disease: the road to cardioprotection. Heart. 2005;91:1621–5.PubMedCrossRefGoogle Scholar
  5. 5.
    Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 2000;348(Pt 3):607–14.PubMedCrossRefGoogle Scholar
  6. 6.
    Hundal RS, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, Inzucchi SE, Schumann WC, Petersen KF, Landau BR, Shulman GI. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes. 2000;49:2063–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Galuska D, Nolte LA, Zierath JR, Wallberg-Henriksson H. Effect of metformin on insulin-stimulated glucose transport in isolated skeletal muscle obtained from patients with NIDDM. Diabetologia. 1994;37:826–32.PubMedCrossRefGoogle Scholar
  8. 8.
    Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108:1167–74.PubMedGoogle Scholar
  9. 9.
    Solskov L, Lofgren B, Kristiansen SB, Jessen N, Pold R, Nielsen TT, Botker HE, Schmitz O, Lund S. Metformin induces cardioprotection against ischaemia/reperfusion injury in the rat heart 24 hours after administration. Basic Clin Pharmacol Toxicol. 2008;103:82–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Calvert JW, Gundewar S, Jha S, Greer JJ, Bestermann WH, Tian R, Lefer DJ. Acute metformin therapy confers cardioprotection against myocardial infarction via AMPK-eNOS-mediated signaling. Diabetes. 2008;57:696–705.PubMedCrossRefGoogle Scholar
  11. 11.
    Paiva MA, Rutter-Locher Z, Goncalves LM, Providencia LA, Davidson SM, Yellon DM, Mocanu MM. Enhancing AMPK activation during ischemia protects the diabetic heart against reperfusion injury. Am J Physiol Heart Circ Physiol. 2011;300:H2123–34.PubMedCrossRefGoogle Scholar
  12. 12.
    Mensah K, Mocanu MM, Yellon DM. Failure to protect the myocardium against ischemia/reperfusion injury after chronic atorvastatin treatment is recaptured by acute atorvastatin treatment: a potential role for phosphatase and tensin homolog deleted on chromosome ten? J Am Coll Cardiol. 2005;45:1287–91.PubMedCrossRefGoogle Scholar
  13. 13.
    Mocanu MM, Yellon DM. PTEN, the Achilles’ heel of myocardial ischaemia/reperfusion injury? Br J Pharmacol. 2007;150:833–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Teresi RE, Shaiu CW, Chen CS, Chatterjee VK, Waite KA, Eng C. Increased PTEN expression due to transcriptional activation of PPARgamma by Lovastatin and Rosiglitazone. Int J Cancer. 2006;118:2390–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Suwa M, Egashira T, Nakano H, Sasaki H, Kumagai S. Metformin increases the PGC-1alpha protein and oxidative enzyme activities possibly via AMPK phosphorylation in skeletal muscle in vivo. J Appl Physiol. 2006;101:1685–92.PubMedCrossRefGoogle Scholar
  16. 16.
    Liang H, Ward WF. PGC-1alpha: a key regulator of energy metabolism. Adv Physiol Educ. 2006;30:145–51.PubMedCrossRefGoogle Scholar
  17. 17.
    Duncan JG, Fong JL, Medeiros DM, Finck BN, Kelly DP. Insulin-resistant heart exhibits a mitochondrial biogenic response driven by the peroxisome proliferator-activated receptor-alpha/PGC-1alpha gene regulatory pathway. Circulation. 2007;115:909–17.PubMedCrossRefGoogle Scholar
  18. 18.
    Zorzano A, Hernandez-Alvarez MI, Palacin M, Mingrone G. Alterations in the mitochondrial regulatory pathways constituted by the nuclear co-factors PGC-1alpha or PGC-1beta and mitofusin 2 in skeletal muscle in type 2 diabetes. Biochim Biophys Acta. 2010;1797:1028–33.PubMedCrossRefGoogle Scholar
  19. 19.
    Patti ME, Butte AJ, Crunkhorn S, Cusi K, Berria R, Kashyap S, Miyazaki Y, Kohane I, Costello M, Saccone R, Landaker EJ, Goldfine AB, Mun E, DeFronzo R, Finlayson J, Kahn CR, Mandarino LJ. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Proc Natl Acad Sci U S A. 2003;100:8466–71.PubMedCrossRefGoogle Scholar
  20. 20.
    Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstrale M, Laurila E, Houstis N, Daly MJ, Patterson N, Mesirov JP, Golub TR, Tamayo P, Spiegelman B, Lander ES, Hirschhorn JN, Altshuler D, Groop LC. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet. 2003;34:267–73.PubMedCrossRefGoogle Scholar
  21. 21.
    Gundewar S, Calvert JW, Jha S, Toedt-Pingel I, Ji SY, Nunez D, Ramachandran A, Anaya-Cisneros M, Tian R, Lefer DJ. Activation of AMP-activated protein kinase by metformin improves left ventricular function and survival in heart failure. Circ Res. 2009;104:403–11.PubMedCrossRefGoogle Scholar
  22. 22.
    Jahangir A, Sagar S, Terzic A. Aging and cardioprotection. J Appl Physiol. 2007;103:2120–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Reznick RM, Zong H, Li J, Morino K, Moore IK, Yu HJ, Liu ZX, Dong J, Mustard KJ, Hawley SA, Befroy D, Pypaert M, Hardie DG, Young LH, Shulman GI. Aging-associated reductions in AMP-activated protein kinase activity and mitochondrial biogenesis. Cell Metab. 2007;5:151–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Anderson R, Prolla T. PGC-1alpha in aging and anti-aging interventions. Biochim Biophys Acta. 2009;1790:1059–66.PubMedCrossRefGoogle Scholar
  25. 25.
    Wenz T. Mitochondria and PGC-1alpha in Aging and Age-Associated Diseases. J Aging Res. 2011;2011:810619.PubMedGoogle Scholar
  26. 26.
    Rees DA, Alcolado JC. Animal models of diabetes mellitus. Diabet Med. 2005;22:359–70.PubMedCrossRefGoogle Scholar
  27. 27.
    Elgebaly MM, Prakash R, Li W, Ogbi S, Johnson MH, Mezzetti EM, Fagan SC, Ergul A. Vascular protection in diabetic stroke: role of matrix metalloprotease-dependent vascular remodeling. J Cereb Blood Flow Metab. 2010;30:1928–38.PubMedCrossRefGoogle Scholar
  28. 28.
    Bell RM, Mocanu MM, Yellon DM. Retrograde heart perfusion: the Langendorff technique of isolated heart perfusion. J Mol Cell Cardiol. 2011;50:940–50.PubMedCrossRefGoogle Scholar
  29. 29.
    Ferrera R, Benhabbouche S, Bopassa JC, Li B, Ovize M. One hour reperfusion is enough to assess function and infarct size with TTC staining in Langendorff rat model. Cardiovasc Drugs Ther. 2009;23:327–31.PubMedCrossRefGoogle Scholar
  30. 30.
    Portha B, Serradas P, Bailbe D, Suzuki K, Goto Y, Giroix MH. Beta-cell insensitivity to glucose in the GK rat, a spontaneous nonobese model for type II diabetes. Diabetes. 1991;40:486–91.PubMedCrossRefGoogle Scholar
  31. 31.
    Aquilano K, Vigilanza P, Baldelli S, Pagliei B, Rotilio G, Ciriolo MR. Peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC-1alpha) and sirtuin 1 (SIRT1) reside in mitochondria: possible direct function in mitochondrial biogenesis. J Biol Chem. 2010;285:21590–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Anderson RM, Barger JL, Edwards MG, Braun KH, O’Connor CE, Prolla TA, Weindruch R. Dynamic regulation of PGC-1alpha localization and turnover implicates mitochondrial adaptation in calorie restriction and the stress response. Aging Cell. 2008;7:101–11.PubMedCrossRefGoogle Scholar
  33. 33.
    Ventura-Clapier R, Garnier A, Veksler V. Transcriptional control of mitochondrial biogenesis: the central role of PGC-1alpha. Cardiovasc Res. 2008;79:208–17.PubMedCrossRefGoogle Scholar
  34. 34.
    Wilcock C, Bailey CJ. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica. 1994;24:49–57.PubMedCrossRefGoogle Scholar
  35. 35.
    Foretz M, Hebrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G, Sakamoto K, Andreelli F, Viollet B. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest. 2010;120:2355–69.PubMedCrossRefGoogle Scholar
  36. 36.
    Wilcock C, Bailey CJ. Sites of metformin-stimulated glucose metabolism. Biochem Pharmacol. 1990;39:1831–4.PubMedCrossRefGoogle Scholar
  37. 37.
    Katakam PV, Ujhelyi MR, Hoenig M, Miller AW. Metformin improves vascular function in insulin-resistant rats. Hypertension. 2000;35:108–12.PubMedCrossRefGoogle Scholar
  38. 38.
    Verma S, Bhanot S, McNeill JH. Metformin decreases plasma insulin levels and systolic blood pressure in spontaneously hypertensive rats. Am J Physiol. 1994;267:H1250–3.PubMedGoogle Scholar
  39. 39.
    Penicaud L, Hitier Y, Ferre P, Girard J. Hypoglycaemic effect of metformin in genetically obese (fa/fa) rats results from an increased utilization of blood glucose by intestine. Biochem J. 1989;262:881–5.PubMedGoogle Scholar
  40. 40.
    MacDonald MR, Eurich DT, Majumdar SR, Lewsey JD, Bhagra S, Jhund PS, Petrie MC, McMurray JJ, Petrie JR, McAlister FA. Treatment of type 2 diabetes and outcomes in patients with heart failure: a nested case-control study from the U.K. General Practice Research Database. Diabetes Care. 2010;33:1213–8.PubMedCrossRefGoogle Scholar
  41. 41.
    Bhamra GS, Hausenloy DJ, Davidson SM, Carr RD, Paiva M, Wynne AM, Mocanu MM, Yellon DM. Metformin protects the ischemic heart by the Akt-mediated inhibition of mitochondrial permeability transition pore opening. Basic Res Cardiol. 2008;103:274–84.PubMedCrossRefGoogle Scholar
  42. 42.
    El MS, Rongen GA, de Boer RA, Riksen NP. The cardioprotective effects of metformin. Curr Opin Lipidol. 2011.Google Scholar
  43. 43.
    Paiva MA, Goncalves LM, Providencia LA, Davidson SM, Yellon DM, Mocanu MM. Transitory activation of AMPK at reperfusion protects the ischaemic-reperfused rat myocardium against infarction. Cardiovasc Drugs Ther. 2010;24:25–32.PubMedCrossRefGoogle Scholar
  44. 44.
    Musi N, Hirshman MF, Nygren J, Svanfeldt M, Bavenholm P, Rooyackers O, Zhou G, Williamson JM, Ljunqvist O, Efendic S, Moller DE, Thorell A, Goodyear LJ. Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes. 2002;51:2074–81.PubMedCrossRefGoogle Scholar
  45. 45.
    Hauton D. Does long-term metformin treatment increase cardiac lipoprotein lipase? Metabolism. 2011;60:32–42.PubMedCrossRefGoogle Scholar
  46. 46.
    Scarpello JH, Howlett HC. Metformin therapy and clinical uses. Diab Vasc Dis Res. 2008;5:157–67.PubMedCrossRefGoogle Scholar
  47. 47.
    Horman S, Beauloye C, Vanoverschelde JL, Bertrand L. AMP-activated protein kinase in the control of cardiac metabolism and remodeling. Curr Heart Fail Rep. 2012;9:164–73.PubMedCrossRefGoogle Scholar
  48. 48.
    Miller RA, Birnbaum MJ. An energetic tale of AMPK-independent effects of metformin. J Clin Invest. 2010;120:2267–70.PubMedCrossRefGoogle Scholar
  49. 49.
    Fernandez-Marcos PJ, Auwerx J. Regulation of PGC-1alpha, a nodal regulator of mitochondrial biogenesis. Am J Clin Nutr. 2011;93:884S–90.PubMedCrossRefGoogle Scholar
  50. 50.
    Suwa M, Nakano H, Kumagai S. Effects of chronic AICAR treatment on fiber composition, enzyme activity, UCP3, and PGC-1 in rat muscles. J Appl Physiol. 2003;95:960–8.PubMedGoogle Scholar
  51. 51.
    Jager S, Handschin C, St-Pierre J, Spiegelman BM. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci U S A. 2007;104:12017–22.PubMedCrossRefGoogle Scholar
  52. 52.
    Liesa M, Palacin M, Zorzano A. Mitochondrial dynamics in mammalian health and disease. Physiol Rev. 2009;89:799–845.PubMedCrossRefGoogle Scholar
  53. 53.
    Soriano FX, Liesa M, Bach D, Chan DC, Palacin M, Zorzano A. Evidence for a mitochondrial regulatory pathway defined by peroxisome proliferator-activated receptor-gamma coactivator-1 alpha, estrogen-related receptor-alpha, and mitofusin 2. Diabetes. 2006;55:1783–91.PubMedCrossRefGoogle Scholar
  54. 54.
    Bach D, Naon D, Pich S, Soriano FX, Vega N, Rieusset J, Laville M, Guillet C, Boirie Y, Wallberg-Henriksson H, Manco M, Calvani M, Castagneto M, Palacin M, Mingrone G, Zierath JR, Vidal H, Zorzano A. Expression of Mfn2, the Charcot-Marie-Tooth neuropathy type 2A gene, in human skeletal muscle: effects of type 2 diabetes, obesity, weight loss, and the regulatory role of tumor necrosis factor alpha and interleukin-6. Diabetes. 2005;54:2685–93.PubMedCrossRefGoogle Scholar
  55. 55.
    Attie AD, Kendziorski CM. PGC-1alpha at the crossroads of type 2 diabetes. Nat Genet. 2003;34:244–5.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Hannah J. Whittington
    • 1
  • Andrew R. Hall
    • 1
  • Catarina P. McLaughlin
    • 1
  • Derek J. Hausenloy
    • 1
  • Derek M. Yellon
    • 1
    • 2
  • Mihaela M. Mocanu
    • 1
  1. 1.The Hatter Cardiovascular Institute, Institute of Cardiovascular Science, UCLLondonUK
  2. 2.The Hatter Cardiovascular InstituteUniversity College LondonLondonUK

Personalised recommendations

Cite article

Buy options