Histochemistry and Cell Biology

, Volume 152, Issue 3, pp 217–225 | Cite as

GSK3β and MCL-1 mediate cardiomyocyte apoptosis in response to high glucose

  • Dongmei Su
  • Jing Zhao
  • Shanshan Hu
  • Lina Guan
  • Qian Li
  • Cuige Shi
  • Xu MaEmail author
  • Jianjun GouEmail author
  • Yunjun ZhouEmail author
Original Paper


Gestational diabetes mellitus is a risk factor for congenital heart defects. Our previous results indicated that a decrease in myocardial cells and an increase in apoptotic cells leads to heart defects under hyperglycemia, but much work remains to elucidate this important mechanism of myocardial cell apoptosis induced by high glucose (HG). In this study, we found that a decrease in GSK3β phosphorylation on Ser9 occurred concomitantly with HG-induced cardiomyocyte apoptosis and in the heart tissues of the offspring of diabetic rats in vitro and in vivo. Decreases in GSK3β (Ser9) phosphorylation in response to HG were remarkably restored after treatment with SC79, an activator of the Akt signaling pathway. SB216763, an effective inhibitor of the GSK3β signaling pathway, suppressed HG-induced apoptosis in cardiomyocytes. Further studies showed a decrease in the expression of the anti-apoptotic protein MCL-1 was associated with GSK3β-mediated apoptosis. MCL-1 overexpression partly inhibits HG-induced apoptosis in cardiomyocytes. Herein, this study revealed the roles of GSK3β and MCL-1 in modulating HG-induced cardiomyocyte apoptosis and maternal diabetes-induced abnormalities.


Cardiomyocyte apoptosis Congenital heart disease High glucose GSK3β MCL-1 



We are grateful to everyone who helped complete this research successfully. We especially, thank professor Ma for supporting the research and Lina Guan, who helped us in many experiments.


This research was supported by grants from the National Natural Science Foundation of China (Grant No. 31871391), the Central Public interest Scientific Institution Basal Research Fund (Grant No. 2018GJZ01), and the National Key Research and Development Program of China (Grant No. 2016YFC1000307, YCZYPT [2018]).

Compliance with ethical standards

Conflict of interest

We declare that there are no conflicts of interests.

Supplementary material

418_2019_1798_MOESM1_ESM.pdf (138 kb)
Supplementary material 1 (PDF 137 kb)


  1. Alqudah MAY, Mansour HT, Mhaidat N (2018) Simvastatin enhances irinotecan-induced apoptosis in prostate cancer via inhibition of MCL-1. Saudi Pharm J 26(2):191–197. CrossRefPubMedGoogle Scholar
  2. Cheng Y, Xia Z, Han Y, Rong J (2016) Plant natural product formononetin protects rat cardiomyocyte H9c2 cells against oxygen glucose deprivation and reoxygenation via Inhibiting ROS formation and promoting GSK-3β phosphorylation. Oxid Med Cell Longev 2016:2060874. CrossRefPubMedPubMedCentralGoogle Scholar
  3. Coghlan MP, Culbert AA, Cross DA, Corcoran SL, Yates JW, Pearce NJ, Rausch OL, Murphy GJ, Carter PS, Roxbee Cox L, Mills D, Brown MJ, Haigh D, Ward RW, Smith DG, Murray KJ, Reith AD, Holder JC (2000) Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. Chem Biol. 7(10):793–803.
  4. Correa A, Gilboa SM, Besser LM, Botto LD, Moore CA, Hobbs CA, Cleves MA, Riehle-Colarusso TJ, Waller DK, Reece EA (2008) Diabetes mellitus and birth defects. Am J Obstet Gynecol. 199(3):237.e1–237.e9. CrossRefGoogle Scholar
  5. Ding Q, He X, Hsu JM, Xia W, Chen CT, Li LY, Lee DF, Liu JC, Zhong Q, Wang X, Hung MC (2007) Degradation of Mcl-1 by beta-TrCP mediates glycogen synthase kinase 3-induced tumor suppression and chemosensitization. Mol Cell Biol 27:4006–4017. CrossRefPubMedGoogle Scholar
  6. Dong M, Hu N, Hua Y, Xu X, Kandadi MR, Guo R, Jiang S, Nair S, Hu D (1832) Ren J (2013) chronic Akt activation attenuated lipopolysaccharide-induced cardiac dysfunction via Akt/GSK3β-dependent inhibition of apoptosis and ER stress. Biochim Biophys Acta 6:848–863. CrossRefGoogle Scholar
  7. Fulda S (2013) Modulation of mitochondrial apoptosis by PI3 K inhibitors. Mitochondrion 13(3):195–198. CrossRefPubMedGoogle Scholar
  8. Gutierrez JC, Prater MR, Smith BJ, Freeman LE, Mallela MK, Holladay SD (2009) Late-gestation ventricular myocardial reduction in fetuses of hyperglycemic CD1 mice is associated with increased apoptosis. Birth Defects Res B Dev Reprod Toxicol 86(5):409–415. CrossRefPubMedPubMedCentralGoogle Scholar
  9. Haruki K, Shiba H, Shimada Y, Shirai Y, Iwase R, Fujiwara Y, Uwagawa T, Ohashi T, Yanaga K (2017) Glycogen synthase kinase-3β activity plays a key role in the antitumor effect of nafamostat mesilate in pancreatic cancer cells. Ann Gastroenterol Surg 2(1):65–71. CrossRefPubMedPubMedCentralGoogle Scholar
  10. Johnson-Farley NN, Patel K, Kim D, Cowen DS (2007) Interaction of FGF-2 with IGF-1 and BDNF in stimulating Akt, ERK, and neuronal survival in hippocampal cultures. Brain Res 1154(1):40–49. CrossRefPubMedPubMedCentralGoogle Scholar
  11. Jope RS, Yuskaitis CJ, Beurel E (2007) Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics. Neurochem Res 32(4–5):577–595. CrossRefPubMedGoogle Scholar
  12. Kabir ME, Singh H, Lu R, Olde B, Leeb-Lundberg LM, Bopassa JC (2015) G protein-coupled estrogen receptor 1 mediates acute estrogen-induced cardioprotection via MEK/ERK/GSK-3β pathway after ischemia/reperfusion. PLoS One 10(9):e0135988. CrossRefPubMedPubMedCentralGoogle Scholar
  13. Kafi Z, Cheshomi H, Gholami O (2018) Isopenthenyloxycoumarin, arctigenin, and hesperidin modify myeloid cell leukemia type-1 (Mcl-1) gene expression by hormesis in K562 cell line. Dose Response 16(3):1559325818796014. CrossRefPubMedPubMedCentralGoogle Scholar
  14. Lee HC, Tsai JN, Liao PY, Tsai WY, Lin KY, Chuang CC, Sun CK, Chang WC, Tsai HJ (2007) Glycogen synthase kinase 3 alpha and 3 beta have distinct functions during cardiogenesis of zebrafish embryo. BMC Dev Biol 7:93. CrossRefPubMedPubMedCentralGoogle Scholar
  15. Lei Y, Gong L, Tan F, Liu Y, Li S, Shen H, Zhu M, Cai W, Xu F, Hou B, Zhou Y, Han H, Qiu L, Sun H (2019) Vaccarin ameliorates insulin resistance and steatosis by activating the AMPK signaling pathway. Eur J Pharmacol 16(851):13–24. CrossRefGoogle Scholar
  16. Lin KT, Hsu SW, Lai FY, Chang TC, Shi LS, Lee SY (2016) Rhodiola crenulata extract regulates hepatic glycogen and lipid metabolism via activation of the AMPK pathway.13. BMC Complement Altern Med 17(16):127. CrossRefGoogle Scholar
  17. Maurer U, Charvet C, Wagman AS, Dejardin E, Green DR (2006) Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell 21:749–760. CrossRefPubMedGoogle Scholar
  18. Sevencan A, Misir A, Ucpunar H, Balioğlu MB, Gür V, Akinci S (2018) The incidence and interrelationship of concomitant anomalies in congenital scoliosis. Turk Neurosurg. CrossRefGoogle Scholar
  19. Shete V, Liu N, Jia Y, Viswakarma N, Reddy JK, Thimmapaya B (2018) Mouse cardiac Pde1C is a direct transcriptional target of Pparα. Int J Mol Sci 19(12):3704. CrossRefPubMedCentralGoogle Scholar
  20. Su D, Guan L, Gao Q, Li Q, Shi C, Liu Y, Sun L, Lu C, Ma X (1863) Zhao J (2017) ROCK1/p53/NOXA signaling mediates cardiomyocyte apoptosis in response to high glucose in vitro and vivo. Biochim Biophys Acta 4:936–946. CrossRefGoogle Scholar
  21. Su D, Song JX, Gao Q, Guan L, Li Q, Shi C, Ma X (2016) Cited2 participates in cardiomyocyte apoptosis and maternal diabetes-induced congenital heart abnormality. Biochem Biophys Res Commun 479(4):887–892. CrossRefPubMedGoogle Scholar
  22. Su D, Zhou Y, Hu S, Guan L, Shi C, Wang Q, Chen Y, Lu C, Li Q, Ma X (2017) Role of GAB1/PI3K/AKT signaling high glucose-induced cardiomyocyte apoptosis. Biomed Pharmacother 93:1197–1204. CrossRefPubMedGoogle Scholar
  23. Thirunavukkarasu M, Selvaraju V, Tapias L, Sanchez JA, Palesty JA, Maulik N (2015) Protective effects of Phyllanthus emblica against myocardial ischemia-reperfusion injury: the role of PI3-kinase/glycogen synthase kinase 3β/β-catenin pathway. J Physiol Biochem 71(4):623–633. CrossRefPubMedGoogle Scholar
  24. Ugolkov AV, Matsangou M, Taxter TJ, O’Halloran TV, Cryns VL, Giles FJ, Mazar AP (2018) Aberrant expression of glycogen synthase kinase-3β in human breast and head and neck cancer. Oncol Lett. 16(5):6437–6444. CrossRefPubMedPubMedCentralGoogle Scholar
  25. Wertz IE, Kusam S, Lam C, Okamoto T, Sandoval W, Anderson DJ, Helgason E, Ernst JA, Eby M, Liu J, Belmont LD, Kaminker JS, O’Rourke KM et al (2011) Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature 471:110–114. CrossRefPubMedGoogle Scholar
  26. Wren C, Birrell G, Hawthorne G (2003) Cardiovascular malformations in infants of diabetic mothers, Heart. 89(10): 1217–1220.
  27. Wu D, Pan W (2010) GSK3: a multifaceted kinase in Wnt signalingTrends. Biochem Sci. 35(3):161–168. CrossRefGoogle Scholar
  28. Xie N, Li H, Wei D, LeSage G, Chen L, Wang S, Zhang Y, Chi L, Ferslew K, He L, Chi Z, Yin D (2010) Glycogen synthase kinase-3 and p38 MAPK are required for opioid-induced microglia apoptosis. Neuropharmacology 59(6):444–451. CrossRefPubMedPubMedCentralGoogle Scholar
  29. Zaouali MA, Panisello A, Lopez A, Castro C, Folch E, Carbonell T, Rolo A, Palmeira CM, Garcia-Gil A, Adam R, Roselló-Catafau J (2017) GSK3β and VDAC involvement in ER stress and apoptosis modulation during orthotopic liver transplantation. Int J Mol Sci 18(3):591. CrossRefPubMedCentralGoogle Scholar
  30. Zhang X, Jiang D, Jiang W, Zhao M, Gan J (2015) Role of TLR4-Mediated PI3K/AKT/GSK-3β signaling pathway in apoptosis of rat hepatocytes. Biomed Res Int 2015:631326. CrossRefPubMedPubMedCentralGoogle Scholar
  31. Zhao Z (2010) Cardiac malformations and alteration of TGFb signaling system in diabetic embryopathy. Birth Defects Res 89(2):97e105. CrossRefGoogle Scholar
  32. Zheng K, Zhang Q, Sheng Z, Li Y, Lu HH (2018) Ciliary neurotrophic factor (CNTF) protects myocardial cells from oxygen glucose deprivation (OGD)/Re-oxygenation via activation of Akt-Nrf2 signaling. Cell Physiol Biochem 51(4):1852–1862. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Genetics, Center for Genetics, Health DepartmentNational Research Institute for Family PlanningBeijingChina
  2. 2.Graduate SchoolPeking Union Medical CollegeBeijingChina
  3. 3.Department of CardiologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
  4. 4.Hongqi Hospital of Mudanjiang Medical CollegeMudanjiangChina

Personalised recommendations