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The Impact of Chronic Glycogen Synthase Kinase-3 Inhibition on Remodeling of Normal and Pre-Diabetic Rat Hearts

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Abstract

Purpose

There is an ongoing search for new drugs and drug targets to treat diseases like Alzheimer’s disease, cancer and type 2 diabetes (T2D). Both obesity and T2D are characterized by the development of a cardiomyopathy associated with increased hypertension and compensatory left ventricular hypertrophy.

Small, specific glycogen synthase kinase-3 (GSK-3) inhibitors were developed to replace lithium chloride for use in psychiatric disorders. In addition, they were advocated as treatment for T2D since GSK-3 inhibition improves blood glucose handling. However, GSK-3 is a regulator of hypertrophic signalling in the heart via phosphorylation of NFATc3 and β-catenin respectively. In view of this, we hypothesized that chronic inhibition of GSK-3 will induce myocardial hypertrophy or exacerbate existing hypertrophy.

Methods

Rats with obesity-induced prediabetes were treated orally with GSK-3 inhibitor (CHIR118637 (CT20026)), 30 mg/kg/day for the last 8 weeks of a 20-week diet high in sugar content vs a control diet. Biometric and biochemical parameters were measured, echocardiography performed and localization and co-localization of NFATc3 and GATA4 determined in cardiomyocytes.

Results

Obesity initiated myocardial hypertrophy, evidenced by increased ventricular mass (1.158 ± 0.029 vs 0.983 ± 0.03 g) and enlarged cardiomyocytes (18.86 ± 2.25 vs 14.92 ± 0.50um2) in association with increased end-diastolic diameter (EDD = 8.48 ± 0.11 vs 8.15 ± 0.10 mm). GSK-3 inhibition (i) increased ventricular mass only in controls (1.075 ± 0.022 g) and (ii) EDD in both groups (controls: 8.63 ± 0.07; obese: 8.72 ± 0.15 mm) (iii) localized NFATc3 and GATA4 peri-nuclearly.

Conclusion

Indications of onset of myocardial hypertrophy in both control and obese rats treated with a GSK-3 inhibitor were found. It remains speculation whether these changes were adaptive or maladaptive.

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References

  1. Alexander JK. The cardiomyopathy of obesity. Prog Cardiovasc Dis. 1985;27:325–34.

    Article  CAS  PubMed  Google Scholar 

  2. Licata G, Scaglione R, Barbagallo M, Parrinello G, Capuana G, Lipari R, Merlino G, Ganguzza A. Effect of obesity on left ventricular functional studies by radionuclide angiocardiography. Int J Obes. 1991;15:295–302.

    CAS  PubMed  Google Scholar 

  3. Devitiis O, Fazio S, Petitto M, Maddalena G, Contaldo F, Mancini M. Obesity and cardiac function. Circulation. 1981;64:477–82.

    Article  Google Scholar 

  4. Messerli FH, Ventura HO, Reisin E, Dreslinki GR, Dunn FG, Mac Phee AA, Frohlich ED. Borderline hypertension and obesity: two prehypertensive states with elevated cardiac output. Circulation. 1982;66:55–60.

    Article  CAS  PubMed  Google Scholar 

  5. Opie LH. The heart: Physiology from cell to circulation. Second ed. New York: Raven Press; 1991. p. p184–5 .p396–400

    Google Scholar 

  6. Ahuja P, Sdek P, Maclellan WD. Cardiac myocyte cell cycle control in development, disease and regeneration. Physiol Rev. 2007;87:521–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bernardo BC, Weeks KL, Pretorius L, McMullen JR. Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies. Pharmacol Ther. 2010;128:191–227.

    Article  CAS  PubMed  Google Scholar 

  8. Haq S, Choukroun G, Ranu H, et al. Glycogen synthase kinase-3β is a negative regulator of cardiomyocyte hypertrophy. J Cell Biol. 2000;151:117–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Antos CL, McKinsey TA, Frey N, et al. Activated glycogen synthase-3β suppresses cardiac hypertrophy in vivo. Proc Natl Acad Sci U S A. 2002;99:907–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Molkentin JD, Lu JR, Antos CL, Markham B, Richardson J, Robbins J, Grant SR, Olson EN. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell. 1998;93:215–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Huisamen B, Lochner A. GSK-3 protein and the heart – friend of foe? SA Heart. 2010;7:48–57.

    Google Scholar 

  12. Vollenweider P, Ménard B, Nicod P. Insulin resistance, defective insulin receptor substrate 2-associated phosphatidylinositol-3' kinase activation, and impaired atypical protein kinase C (zeta/lambda) activation in myotubes from obese patients with impaired glucose tolerance. Diabetes. 2002;51(4):1052–9.

    Article  CAS  PubMed  Google Scholar 

  13. Huisamen B. Protein kinase B in the diabetic heart – an invited publication. J Mol Cell Biochem. 2003;249:31–8.

    Article  CAS  Google Scholar 

  14. Henriksen EJ, Dokken BB. Role of glycogen synthase kinase-3 in insulin resistance and type 2 diabetes. Curr Drug Targets. 2006;7:1435–41.

    Article  CAS  PubMed  Google Scholar 

  15. Van Wauwe J, Haefner B. Glycogen synthase kinase-3 as drug target: from wallflower to center of attention. Drug News Perspect. 2003;16:557–65.

    Article  PubMed  Google Scholar 

  16. Meijer L, Flajolet M, Greengard P. Pharmacological inhibitors of glycogen synthase kinase 3. Trends Pharmacol Sci. 2004;25:471–80.

    Article  CAS  PubMed  Google Scholar 

  17. Klein PS, Melton DA. A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci U S A. 1996;93:8455–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wagman AS, Johnson KW, Bussiere DE. Discovery and development of GSK3 inhibitors for the treatment of type 2 diabetes. Curr Pharm Des. 2004;10:1105–37.

    Article  CAS  PubMed  Google Scholar 

  19. Lal H, Ahmad F, Woodgett J, Force T. The GSK-3 family as therapeutic target for myocardial diseases. Circ Res. 2015;116:138–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Juhaszova M, Zorov DB, Kim SH, Pepe S, Fu Q, Fishbein KW, Ziman BD, Wang S, Ytrehus K, Antor CL, Olson EN, Solott SJ. Glycogen synthase kinase-3beta mediates convergence of protection signalling to inhibit the mitochondrial permeability transition pore. J Clin Invest. 2004;113:1535–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gomez L, Paillard M, Thibault H, Derumeaux G, Ovize M. Inhibition of GSK3beta by postconditioning is required to prevent opening of the mitochondrial permeability transition pore during reperfusion. Circulation. 2008;117:2761–8.

    Article  CAS  PubMed  Google Scholar 

  22. Cheng H, Woodgett J, Maamari M, Force T. Targeting GSK-3 family members in the heart: a very sharp double-edged sword. J Mol Cell Cardiol. 2011;51:607–13.

    Article  CAS  PubMed  Google Scholar 

  23. Xia Y, Rao J, Yao A, Zhang F, Li G, Wang X, Lu L. Lithium exacerbates hepatic ischemia/reperfusion injury by inhibiting GSK-3/NF-KB-mediated protective signalling in mice. Eur J Pharmacol. 2012;697:117–25.

    Article  CAS  PubMed  Google Scholar 

  24. Liu A, Fang H, Dahmen U, Dirsch O. Chronic lithium treatment protects against liver ischemia/reperfusion injury in rats. Liver Transpl. 2013;19:762–72.

    Article  PubMed  Google Scholar 

  25. Flepisi TB, Lochner A, Huisamen B. The consequences of long-term glycogen synthase kinase-3 inhibition on normal and insulin resistant rat hearts. Cardiovasc Drugs Ther. 2013;27:381–92.

    Article  CAS  PubMed  Google Scholar 

  26. Cline GW, Johnson K, Regittnig W, Perret P, Tozzo E, Xiao L, et al. Effects of a novel glycogen synthase kinase-3 inhibitor on insulin-stimulated glucose metabolism in Zucker diabetic fatty (fa/fa) rats. Diabetes. 2002;51:2903–10.

    Article  CAS  PubMed  Google Scholar 

  27. Marais E, Genade S, Salie R, Huisamen B, Maritz S, Moolman JA, Lochner A. The temporal relationship between p38 MAPK and HSP27 activation in ischaemic and pharmacological preconditioning. Basic Res Cardiol. 2005;100:35–47.

    Article  CAS  PubMed  Google Scholar 

  28. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anals Biochem. 1976;72:248–54.

    Article  CAS  Google Scholar 

  29. Huisamen B, Genis A, Marais E, Lochner A. Pre-treatment with a DPP-4 inhibitor is infarct sparing in hearts from obese, pre-diabetic rats. Cardiovasc Drugs Ther. 2011;25:13–20.

    Article  CAS  PubMed  Google Scholar 

  30. Bird SD, Doevendans PA. Van Rooijen MA, Brutel de la Riviere a, Hassink RJ, Passier, R, mummery CL. The human adult cardiomyocyte phenotype. Cardiovasc Res. 2003;58:423–34.

    Article  CAS  PubMed  Google Scholar 

  31. Tokudome T, Horio T, Kishimoto I, Soeki T, Mori K, Kawano Y, Kohno M, Garbers DL, Nakao K, Kangawa K. Calcineurin–nuclear factor of activated T cells pathway–dependent cardiac remodeling in mice deficient in guanylyl cyclase a, a receptor for atrial and brain natriuretic peptides. Circulation. 2005;111:3095–104.

    Article  CAS  PubMed  Google Scholar 

  32. Nduhirabandi F, Du Toit EF, Blackhurst D, Marais D, Lochner A. Chronic melatonin consumption prevents obesity-related metabolic abnormalities and protects the heart against myocardial ischemia and reperfusion injury in a prediabetic model of diet-induced obesity. J Pineal Res. 2011;50:171–82.

    CAS  PubMed  Google Scholar 

  33. Wensley I, Salaveria K, Bulmer AC, Donner DG, Du Toit EF. Myocardial structure, function and ischaemic tolerance in a rodent model of obesity with insulin resistance. Exp Physiol. 2013;11:1552–64.

    Article  Google Scholar 

  34. Dokken BB, Sloniger JA, Henriksen EJ. Acute selective glycogen synthase kinase-3 inhibition enhances insulin signaling in prediabetic insulin resistant rat skeletal muscle. Am J Physiol Endocrinol Metal. 2005;288:E1188–94.

    Article  CAS  Google Scholar 

  35. Rao R, Hao CM, Redha R, Wasserman DH, McGuinness OP, Breyer MD. Glycogen synthase kinase 3 inhibition improves insulin-stimulated glucose metabolism but not hypertension in high-fat C57BL/6 J mice. Diabetologia. 2007;50:452–60.

    Article  CAS  PubMed  Google Scholar 

  36. Kaidanovich-Beilin O, Eldar FH. Long-term treatment with novel glycogen synthase kinase-3 inhibitor improves glucose homeostasis in ob/ob mice: molecular characterization in liver and muscle. J Pharmacol Exp Ther. 2006;316:17–24.

    Article  CAS  PubMed  Google Scholar 

  37. Hargreaves M. Interactions between muscle glycogen and blood glucose during exercise. Exerc Sport Sci Rev. 1997;25:21–39.

    Article  CAS  PubMed  Google Scholar 

  38. Eldar-Finkelman H, Krebs EG. Phosphorylation of insulin receptor substrate 1 by glycogen synthase kinase 3 impairs insulin action. Proc Natl Acad Sci U S A. 1997;94:9660–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Stypmann J, Engelen MA, Troatz C, Rothenburger M, Eckard L, Tiemann K. Echocardiographic assessment of global left ventricular function in mice. Lab Anim. 2009;43:127–37.

    Article  CAS  PubMed  Google Scholar 

  40. Rajapurohitam V, Gan XT, Kirshenbaum LA, Karmazyn M. The obesity-associated peptide leptin induces hypertrophy in neonatal rat ventricular myocytes. Circ Res. 2003;93:277–9.

    Article  CAS  PubMed  Google Scholar 

  41. Abe Y, Ono K, Kawamura T, Wada H, Kita T, Shimatsu A, Hasegawa K. Leptin induces elongation of cardiac myocytes and causes eccentric left ventricular dilatation with compensation. Am J Physiol Heart Circ Physiol. 2007;292:H2387–96.

    Article  CAS  PubMed  Google Scholar 

  42. C.R B, C.M S, C.W T, Gardner P, Crabtree GR. Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3. Science. 1997;275:1930–4.

    Article  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Biomedical Sciences, Division of Medical Physiology, Faculty of Medicine and Health Sciences, University of Stellenbosch, P.O. Box 19063, Tygerberg, 7505, Republic of South Africa

    B. Huisamen & A. Lochner

  2. South African Medical Research Council Biomedical Research and Innovation Platform, Tygerberg, 7505, South Africa

    B. Huisamen

  3. Institute for Experimental Medical Research, Oslo University Hospital, Ullevål, Oslo, Norway

    T. Lubelwana Hafver

  4. Imaging Unit – Central analytical Facility, University of Stellenbosch, Stellenbosch, 7600, South Africa

    D. Lumkwana

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  1. B. Huisamen
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  2. T. Lubelwana Hafver
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  3. D. Lumkwana
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  4. A. Lochner
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Correspondence to B. Huisamen.

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Huisamen, B., Hafver, T.L., Lumkwana, D. et al. The Impact of Chronic Glycogen Synthase Kinase-3 Inhibition on Remodeling of Normal and Pre-Diabetic Rat Hearts. Cardiovasc Drugs Ther 30, 237–246 (2016). https://doi.org/10.1007/s10557-016-6665-2

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