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Novel GSK-3β Inhibitor Neopetroside A Protects Against Murine Myocardial Ischemia/Reperfusion InjuryOpen Access

Original Research - Preclinical

J Am Coll Cardiol Basic Trans Science, 7 (11) 1102–1116
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Visual Abstract

Highlights

Neopetroside A preserved cardiac hemodynamics and mitochondrial respiration capacity ex vivo after ischemia/reperfusion injury in rat hearts.

NPS A significantly prevented cardiac fibrosis in vivo in myocardial infarcted mice.

In vivo and ex vivo effects were caused by preserved mitochondrial function.

In vitro kinase screening assays, in silico docking simulation studies, and SPR binding assays demonstrated that NPS A directly interacts with GSK-3β.

GSK-3β inhibition regulates the NAD+/ NADH ratio by activating the Nrf2/Nqo1 axis in a phosphorylation-independent manner.

Summary

Recent trends suggest novel natural compounds as promising treatments for cardiovascular disease. The authors examined how neopetroside A, a natural pyridine nucleoside containing an α-glycoside bond, regulates mitochondrial metabolism and heart function and investigated its cardioprotective role against ischemia/reperfusion injury. Neopetroside A treatment maintained cardiac hemodynamic status and mitochondrial respiration capacity and significantly prevented cardiac fibrosis in murine models. These effects can be attributed to preserved cellular and mitochondrial function caused by the inhibition of glycogen synthase kinase-3 beta, which regulates the ratio of nicotinamide adenine dinucleotide to nicotinamide adenine dinucleotide, reduced, through activation of the nuclear factor erythroid 2–related factor 2/NAD(P)H quinone oxidoreductase 1 axis in a phosphorylation-independent manner.

References

  • 1. Handy D.E., Loscalzo J. "Redox regulation of mitochondrial function". Antioxid Redox Signal 2012;16:1323-1367.

    CrossrefMedlineGoogle Scholar
  • 2. Brown D.A., Perry J.B., Allen M.E., et al. "Expert consensus document: mitochondrial function as a therapeutic target in heart failure". Nat Rev Cardiol 2017;14:238-250.

    CrossrefMedlineGoogle Scholar
  • 3. Oku N., Matsunaga S., van Soest R.W., Fusetani N. "Renieramycin J, a highly cytotoxic tetrahydroisoquinoline alkaloid, from a marine sponge Neopetrosia sp". J Nat Prod 2003;66:1136-1139.

    CrossrefMedlineGoogle Scholar
  • 4. Shubina L.K., Makarieva T.N., Yashunsky D.V., et al. "Pyridine nucleosides neopetrosides A and B from a marine Neopetrosia sp. sponge. Synthesis of neopetroside A and its beta-riboside analogue". J Nat Prod 2015;78:1383-1389.

    CrossrefMedlineGoogle Scholar
  • 5. Ussher J.R., Jaswal J.S., Lopaschuk G.D. "Pyridine nucleotide regulation of cardiac intermediary metabolism". Circ Res 2012;111:628-641.

    CrossrefMedlineGoogle Scholar
  • 6. Stein L.R., Imai S. "The dynamic regulation of NAD metabolism in mitochondria". Trends Endocrinol Metab 2012;23:420-428.

    CrossrefMedlineGoogle Scholar
  • 7. Ying W. "NAD+/NADH and NADP+/NADPH in cellular functions and cell death: regulation and biological consequences". Antioxid Redox Signal 2008;10:179-206.

    CrossrefMedlineGoogle Scholar
  • 8. Jope R.S., Yuskaitis C.J., Beurel E. "Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics". Neurochem Res 2007;32:4-5: 577-595.

    CrossrefMedlineGoogle Scholar
  • 9. Cohen P., Goedert M. "GSK3 inhibitors: development and therapeutic potential". Nat Rev Drug Discov 2004;3:479-487.

    CrossrefMedlineGoogle Scholar
  • 10. Jope R.S., Johnson G.V. "The glamour and gloom of glycogen synthase kinase-3". Trends Biochem Sci 2004;29:95-102.

    CrossrefMedlineGoogle Scholar
  • 11. Miura T., Miki T. "GSK-3beta, a therapeutic target for cardiomyocyte protection". Circ J 2009;73:1184-1192.

    CrossrefMedlineGoogle Scholar
  • 12. Gross E.R., Hsu A.K., Gross G.J. "Opioid-induced cardioprotection occurs via glycogen synthase kinase beta inhibition during reperfusion in intact rat hearts". Circ Res 2004;94:960-966.

    CrossrefMedlineGoogle Scholar
  • 13. Nishihara M., Miura T., Miki T., et al. "Modulation of the mitochondrial permeability transition pore complex in GSK-3beta-mediated myocardial protection". J Mol Cell Cardiol 2007;43:564-570.

    CrossrefMedlineGoogle Scholar
  • 14. Tong H., Imahashi K., Steenbergen C., Murphy E. "Phosphorylation of glycogen synthase kinase-3beta during preconditioning through a phosphatidylinositol-3-kinase–dependent pathway is cardioprotective". Circ Res 2002;90:377-379.

    CrossrefMedlineGoogle Scholar
  • 15. Hu B., Wu Y., Liu J., et al. "GSK-3beta inhibitor induces expression of Nrf2/TrxR2 signaling pathway to protect against renal ischemia/reperfusion injury in diabetic rats". Kidney Blood Press Res 2016;41:937-946.

    CrossrefMedlineGoogle Scholar
  • 16. Tanigawa S., Fujii M., Hou D.X. "Action of Nrf2 and Keap1 in ARE-mediated NQO1 expression by quercetin". Free Radic Biol Med 2007;42:1690-1703.

    CrossrefMedlineGoogle Scholar
  • 17. Chen X., Liu Y., Zhu J., et al. "GSK-3beta downregulates Nrf2 in cultured cortical neurons and in a rat model of cerebral ischemia-reperfusion". Sci Rep 2016;6:20196.

    CrossrefMedlineGoogle Scholar
  • 18. Gao E., Lei Y.H., Shang X., et al. "A novel and efficient model of coronary artery ligation and myocardial infarction in the mouse". Circ Res 2010;107:1445-1453.

    CrossrefMedlineGoogle Scholar
  • 19. Jeong S.H., Song I.S., Kim H.K., et al. "An analogue of resveratrol HS-1793 exhibits anticancer activity against MCF-7 cells via inhibition of mitochondrial biogenesis gene expression". Mol Cells 2012;34:357-365.

    CrossrefMedlineGoogle Scholar
  • 20. Ko T.H., Marquez J.C., Kim H.K., et al. "Resistance exercise improves cardiac function and mitochondrial efficiency in diabetic rat hearts". Pflugers Arch 2018;470:263-275.

    CrossrefMedlineGoogle Scholar
  • 21. Davies S.P., Reddy H., Caivano M., Cohen P. "Specificity and mechanism of action of some commonly used protein kinase inhibitors". Biochem J 2000;351:Pt 1: 95-105.

    CrossrefMedlineGoogle Scholar
  • 22. Thu V.T., Kim H.K., Long le T., et al. "NecroX-5 prevents hypoxia/reoxygenation injury by inhibiting the mitochondrial calcium uniporter". Cardiovasc Res 2012;94:342-350.

    CrossrefMedlineGoogle Scholar
  • 23. Zeng M., Wei X., Wu Z.Y., et al. "Simulated ischemia/reperfusion-induced p65-Beclin 1-dependent autophagic cell death in human umbilical vein endothelial cells". Sci Rep 2016;6:37448.

    CrossrefMedlineGoogle Scholar
  • 24. Morris G.M., Green L.G., Radic Z., et al. "Automated docking with protein flexibility in the design of femtomolar “click chemistry” inhibitors of acetylcholinesterase". J Chem Inf Model 2013;53:898-906.

    CrossrefMedlineGoogle Scholar
  • 25. Bertrand J.A., Thieffine S., Vulpetti A., et al. "Structural characterization of the GSK-3beta active site using selective and non-selective ATP-mimetic inhibitors". J Mol Biol 2003;333:393-407.

    CrossrefMedlineGoogle Scholar
  • 26. Juhaszova M., Zorov D.B., Yaniv Y., et al. "Role of glycogen synthase kinase-3beta in cardioprotection". Circ Res 2009;104:1240-1252.

    CrossrefMedlineGoogle Scholar
  • 27. Maejima Y., Galeotti J., Molkentin J.D., Sadoshima J., Zhai P. "Constitutively active MEK1 rescues cardiac dysfunction caused by overexpressed GSK-3alpha during aging and hemodynamic pressure overload". Am J Physiol Heart Circ Physiol 2012;303:H979-H988.

    CrossrefMedlineGoogle Scholar
  • 28. Zhou J., Freeman T.A., Ahmad F., et al. "GSK-3alpha is a central regulator of age-related pathologies in mice". J Clin Invest 2013;123:1821-1832.

    CrossrefMedlineGoogle Scholar
  • 29. Ahmad F., Singh A.P., Tomar D., et al. "Cardiomyocyte-GSK-3alpha promotes mPTP opening and heart failure in mice with chronic pressure overload". J Mol Cell Cardiol 2019;130:65-75.

    CrossrefMedlineGoogle Scholar
  • 30. Nakamura M., Liu T., Husain S., et al. "Glycogen synthase kinase-3alpha promotes fatty acid uptake and lipotoxic cardiomyopathy". Cell Metab 2019;29:1119-1134.e12.

    CrossrefMedlineGoogle Scholar
  • 31. Ahmad F., Lal H., Zhou J., et al. "Cardiomyocyte-specific deletion of Gsk3alpha mitigates post-myocardial infarction remodeling, contractile dysfunction, and heart failure". J Am Coll Cardiol 2014;64:696-706.

    View ArticleGoogle Scholar
  • 32. Lal H., Zhou J., Ahmad F., et al. "Glycogen synthase kinase-3alpha limits ischemic injury, cardiac rupture, post-myocardial infarction remodeling and death". Circulation 2012;125:65-75.

    CrossrefMedlineGoogle Scholar
  • 33. Antos C.L., McKinsey T.A., Frey N., et al. "Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivo". Proc Natl Acad Sci U S A 2002;99:907-912.

    CrossrefMedlineGoogle Scholar
  • 34. Hirotani S., Zhai P., Tomita H., et al. "Inhibition of glycogen synthase kinase 3beta during heart failure is protective". Circ Res 2007;101:1164-1174.

    CrossrefMedlineGoogle Scholar
  • 35. Murphy E., Steenbergen C. "Inhibition of GSK-3 beta as a target for cardioprotection: the importance of timing, location, duration and degree of inhibition". Exp Opin Ther Targets 2005;9:447-456.

    CrossrefMedlineGoogle Scholar
  • 36. Yang K., Chen Z., Gao J., et al. "The key roles of GSK-3beta in regulating mitochondrial activity". Cell Physiol Biochem 2017;44:1445-1459.

    CrossrefMedlineGoogle Scholar
  • 37. Zhu J., Rebecchi M.J., Glass P.S., Brink P.R., Liu L. "Cardioprotection of the aged rat heart by GSK-3beta inhibitor is attenuated: age-related changes in mitochondrial permeability transition pore modulation". Am J Physiol Heart Circ Physiol 2011;300:H922-H930.

    CrossrefMedlineGoogle Scholar
  • 38. Eldar-Finkelman H., Martinez A. "GSK-3 inhibitors: preclinical and clinical focus on CNS". Front Mol Neurosci 2011;4:32.

    CrossrefMedlineGoogle Scholar
  • 39. Martin S.A., Souder D.C., Miller K.N., et al. "GSK3beta regulates brain energy metabolism". Cell Rep 2018;23:1922-1931.e4.

    CrossrefMedlineGoogle Scholar
  • 40. Walker M.A., Tian R. "Raising NAD in heart failure: time to translate?"Circulation 2018;137:2274-2277.

    CrossrefMedlineGoogle Scholar
  • 41. Canto C., Menzies K.J., Auwerx J. "NAD+ metabolism and the control of energy homeostasis: a balancing act between mitochondria and the nucleus". Cell Metab 2015;22:31-53.

    CrossrefMedlineGoogle Scholar
  • 42. Mericskay M. "Nicotinamide adenine dinucleotide homeostasis and signalling in heart disease: pathophysiological implications and therapeutic potential". Arch Cardiovasc Dis 2016;109:207-215.

    CrossrefMedlineGoogle Scholar
  • 43. Diguet N., Trammell S.A.J., Tannous C., et al. "Nicotinamide riboside preserves cardiac function in a mouse model of dilated cardiomyopathy". Circulation 2018;137:2256-2273.

    CrossrefMedlineGoogle Scholar
  • 44. Lee C.F., Chavez J.D., Garcia-Menendez L., et al. "Normalization of NAD+ redox balance as a therapy for heart failure". Circulation 2016;134:883-894.

    CrossrefMedlineGoogle Scholar
  • 45. Dai X., Yan X., Zeng J., et al. "Elevating CXCR7 improves angiogenic function of EPCs via Akt/GSK-3beta/Fyn-mediated Nrf2 activation in diabetic limb ischemia". Circ Res 2017;120:e7-e23.

    CrossrefMedlineGoogle Scholar
  • 46. Khadka D., Kim H.J., Oh G.S., et al. "Augmentation of NAD+ levels by enzymatic action of NAD(P)H quinone oxidoreductase 1 attenuates Adriamycin-induced cardiac dysfunction in mice". J Mol Cell Cardiol 2018;124:45-57.

    CrossrefMedlineGoogle Scholar
  • 47. Lee T.M., Lin S.Z., Chang N.C. "Antiarrhythmic effect of lithium in rats after myocardial infarction by activation of Nrf2/HO-1 signaling". Free Radic Biol Med 2014;77:71-81.

    CrossrefMedlineGoogle Scholar
  • 48. Lam A.P., Gottardi C.J. "β-Catenin signaling: a novel mediator of fibrosis and potential therapeutic target". Curr Opin Rheumatol 2011;23:562-567.

    CrossrefMedlineGoogle Scholar
  • 49. Lehwald N., Tao G.Z., Jang K.Y., et al. "β-Catenin regulates hepatic mitochondrial function and energy balance in mice". Gastroenterology 2012;143:754-764.

    CrossrefMedlineGoogle Scholar