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Cardiovascular Drugs and Therapy
Published in: Cardiovascular Drugs and Therapy 1/2013

01-02-2013 | ORIGINAL ARTICLE

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

Authors: Hannah J. Whittington, Andrew R. Hall, Catarina P. McLaughlin, Derek J. Hausenloy, Derek M. Yellon, Mihaela M. Mocanu

Published in: Cardiovascular Drugs and Therapy | Issue 1/2013

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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.
Literature
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
4.
Monteiro P, Goncalves L, Providencia LA. Diabetes and cardiovascular disease: the road to cardioprotection. Heart. 2005;91:1621–5.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMed
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
13.
Mocanu MM, Yellon DM. PTEN, the Achilles’ heel of myocardial ischaemia/reperfusion injury? Br J Pharmacol. 2007;150:833–8.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
16.
Liang H, Ward WF. PGC-1alpha: a key regulator of energy metabolism. Adv Physiol Educ. 2006;30:145–51.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
22.
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.PubMedCrossRef
24.
Anderson R, Prolla T. PGC-1alpha in aging and anti-aging interventions. Biochim Biophys Acta. 2009;1790:1059–66.PubMedCrossRef
25.
Wenz T. Mitochondria and PGC-1alpha in Aging and Age-Associated Diseases. J Aging Res. 2011;2011:810619.PubMed
26.
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
34.
Wilcock C, Bailey CJ. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica. 1994;24:49–57.PubMedCrossRef
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.PubMedCrossRef
36.
Wilcock C, Bailey CJ. Sites of metformin-stimulated glucose metabolism. Biochem Pharmacol. 1990;39:1831–4.PubMedCrossRef
37.
Katakam PV, Ujhelyi MR, Hoenig M, Miller AW. Metformin improves vascular function in insulin-resistant rats. Hypertension. 2000;35:108–12.PubMedCrossRef
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.PubMed
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.PubMed
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.PubMedCrossRef
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.PubMedCrossRef
42.
El MS, Rongen GA, de Boer RA, Riksen NP. The cardioprotective effects of metformin. Curr Opin Lipidol. 2011.
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.PubMedCrossRef
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.PubMedCrossRef
45.
Hauton D. Does long-term metformin treatment increase cardiac lipoprotein lipase? Metabolism. 2011;60:32–42.PubMedCrossRef
46.
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.PubMedCrossRef
48.
Miller RA, Birnbaum MJ. An energetic tale of AMPK-independent effects of metformin. J Clin Invest. 2010;120:2267–70.PubMedCrossRef
49.
Fernandez-Marcos PJ, Auwerx J. Regulation of PGC-1alpha, a nodal regulator of mitochondrial biogenesis. Am J Clin Nutr. 2011;93:884S–90.PubMedCrossRef
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.PubMed
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.PubMedCrossRef
52.
Liesa M, Palacin M, Zorzano A. Mitochondrial dynamics in mammalian health and disease. Physiol Rev. 2009;89:799–845.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
55.
Attie AD, Kendziorski CM. PGC-1alpha at the crossroads of type 2 diabetes. Nat Genet. 2003;34:244–5.PubMedCrossRef
Metadata
Title
Chronic Metformin Associated Cardioprotection Against Infarction: Not Just a Glucose Lowering Phenomenon
Authors
Hannah J. Whittington
Andrew R. Hall
Catarina P. McLaughlin
Derek J. Hausenloy
Derek M. Yellon
Mihaela M. Mocanu
Publication date
01-02-2013
Publisher
Springer US
Published in
Cardiovascular Drugs and Therapy / Issue 1/2013
Print ISSN: 0920-3206
Electronic ISSN: 1573-7241
DOI
https://doi.org/10.1007/s10557-012-6425-x

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