Skip to main content

Advertisement

SpringerLink
Log in

GDH promotes isoprenaline-induced cardiac hypertrophy by activating mTOR signaling via elevation of α-ketoglutarate level

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

Numerous studies reveal that metabolism dysfunction contributes to the development of pathological cardiac hypertrophy. While the abnormal lipid and glucose utilization in cardiomyocytes responding to hypertrophic stimuli have been extensively studied, the alteration and implication of glutaminolysis are rarely discussed. In the present work, we provide the first evidence that glutamate dehydrogenase (GDH), an enzyme that catalyzes conversion of glutamate into ɑ-ketoglutarate (AKG), participates in isoprenaline (ISO)-induced cardiac hypertrophy through activating mammalian target of rapamycin (mTOR) signaling. The expression and activity of GDH were enhanced in cultured cardiomyocytes and rat hearts following ISO treatment. Overexpression of GDH, but not its enzymatically inactive mutant, provoked cardiac hypertrophy. In contrast, GDH knockdown could relieve ISO-triggered hypertrophic responses. The intracellular AKG level was elevated by ISO or GDH overexpression, which led to increased phosphorylation of mTOR and downstream effector ribosomal protein S6 kinase (S6K). Exogenous supplement of AKG also resulted in mTOR activation and cardiomyocyte hypertrophy. However, incubation with rapamycin, an mTOR inhibitor, attenuated hypertrophic responses in cardiomyocytes. Furthermore, GDH silencing protected rats from ISO-induced cardiac hypertrophy. These findings give a further insight into the role of GDH in cardiac hypertrophy and suggest it as a potential target for hypertrophy-related cardiomyopathy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

The data and materials used during the current study are available from the corresponding author on reasonable request.

References

  • Asadi Shahmirzadi A, Edgar D, Liao CY, Hsu YM, Lucanic M, Asadi Shahmirzadi A, Wiley CD, Gan G, Kim DE, Kasler HG, Kuehnemann C, Kaplowitz B, Bhaumik D, Riley RR, Kennedy BK, Lithgow GJ (2020) Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice. Cell Metab 32:447-456 e446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Carey BW, Finley LW, Cross JR, Allis CD, Thompson CB (2015) Intracellular alpha-ketoglutarate maintains the pluripotency of embryonic stem cells. Nature 518:413–416

    Article  CAS  PubMed  Google Scholar 

  • Carobbio S, Frigerio F, Rubi B, Vetterli L, Bloksgaard M, Gjinovci A, Pournourmohammadi S, Herrera PL, Reith W, Mandrup S, Maechler P (2009) Deletion of glutamate dehydrogenase in beta-cells abolishes part of the insulin secretory response not required for glucose homeostasis. J Biol Chem 284:921–929

    Article  CAS  PubMed  Google Scholar 

  • Chen PA, Xu ZH, Huang YL, Luo Y, Zhu DJ, Wang P, Du ZY, Yang Y, Wu DH, Lai WY, Ren H, Xu DL (2014a) Increased serum 2-oxoglutarate associated with high myocardial energy expenditure and poor prognosis in chronic heart failure patients. Biochim Biophys Acta 1842:2120–2125

    Article  CAS  PubMed  Google Scholar 

  • Chen X, Zeng S, Zou J, Chen Y, Yue Z, Gao Y, Zhang L, Cao W, Liu P (2014b) Rapamycin attenuated cardiac hypertrophy induced by isoproterenol and maintained energy homeostasis via inhibiting NF-kappaB activation. Mediators Inflamm 2014:868753

    Article  PubMed  PubMed Central  Google Scholar 

  • Cluntun AA, Badolia R, Lettlova S, Parnell KM, Shankar TS, Diakos NA, Olson KA, Taleb I, Tatum SM, Berg JA, Cunningham CN, Van Ry T, Bott AJ, Krokidi AT, Fogarty S, Skedros S, Swiatek WI, Yu X, Luo B, Merx S, Navankasattusas S, Cox JE, Ducker GS, Holland WL, McKellar SH, Rutter J, Drakos SG (2021) The pyruvate-lactate axis modulates cardiac hypertrophy and heart failure. Cell Metab 33:629-648 e610

    Article  CAS  PubMed  Google Scholar 

  • Colombo F, Gosselin H, El-Helou V, Calderone A (2003) Beta-adrenergic receptor-mediated DNA synthesis in neonatal rat cardiac fibroblasts proceeds via a phosphatidylinositol 3-kinase dependent pathway refractory to the antiproliferative action of cyclic AMP. J Cell Physiol 195:322–330

    Article  CAS  PubMed  Google Scholar 

  • Ding YQ, Zhang YH, Lu J, Li B, Yu WJ, Yue ZB, Hu YH, Wang PX, Li JY, Cai SD, Ye JT, Liu PQ (2021) MicroRNA-214 contributes to Ang II-induced cardiac hypertrophy by targeting SIRT3 to provoke mitochondrial malfunction. Acta Pharmacol Sin 42:1422–1436

    Article  CAS  PubMed  Google Scholar 

  • Drews L, Zimmermann M, Westhoff P, Brilhaus D, Poss RE, Bergmann L, Wiek C, Brenneisen P, Piekorz RP, Mettler-Altmann T, Weber APM, Reichert AS (2020) Ammonia inhibits energy metabolism in astrocytes in a rapid and glutamate dehydrogenase 2-dependent manner. Dis Model Mech 13:047134

    Article  Google Scholar 

  • Dunn WB, Broadhurst DI, Deepak SM, Buch MH, McDowell G, Spasic I, Ellis DI, Brooks N, Kell DB, Neyses L (2007) Serum metabolomics reveals many novel metabolic markers of heart failure, including pseudouridine and 2-oxoglutarate. Metabolomics 3:413–426

    Article  CAS  Google Scholar 

  • Duran RV, Oppliger W, Robitaille AM, Heiserich L, Skendaj R, Gottlieb E, Hall MN (2012) Glutaminolysis activates Rag-mTORC1 signaling. Mol Cell 47:349–358

    Article  CAS  PubMed  Google Scholar 

  • Durante W (2019) The emerging role of l-glutamine in cardiovascular health and disease. Nutrients 11:2092

    Article  CAS  PubMed Central  Google Scholar 

  • Fan J, Kamphorst JJ, Mathew R, Chung MK, White E, Shlomi T, Rabinowitz JD (2013) Glutamine-driven oxidative phosphorylation is a major ATP source in transformed mammalian cells in both normoxia and hypoxia. Mol Syst Biol 9:712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gao L, Guo Y, Liu X, Shang D, Du Y (2017) KLF15 protects against isoproterenol-induced cardiac hypertrophy via regulation of cell death and inhibition of Akt/mTOR signaling. Biochem Biophys Res Commun 487:22–27

    Article  CAS  PubMed  Google Scholar 

  • Hasumi Y, Baba M, Hasumi H, Huang Y, Lang M, Reindorf R, Oh HB, Sciarretta S, Nagashima K, Haines DC, Schneider MD, Adelstein RS, Schmidt LS, Sadoshima J, Marston Linehan W (2014) Folliculin (Flcn) inactivation leads to murine cardiac hypertrophy through mTORC1 deregulation. Hum Mol Genet 23:5706–5719

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • He Y, Lang X, Cheng D, Zhang T, Yang Z, Xiong R (2020) miR30a5p inhibits hypoxia/reoxygenationinduced oxidative stress and apoptosis in HK2 renal tubular epithelial cells by targeting glutamate dehydrogenase 1 (GLUD1). Oncol Rep 44:1539–1549

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jin L, Chun J, Pan C, Kumar A, Zhang G, Ha Y, Li D, Alesi GN, Kang Y, Zhou L, Yu WM, Magliocca KR, Khuri FR, Qu CK, Metallo C, Owonikoko TK, Kang S (2018) The PLAG1-GDH1 axis promotes Anoikis resistance and tumor metastasis through CamKK2-AMPK signaling in LKB1-deficient lung cancer. Mol Cell 69:87-99 e87

    Article  CAS  PubMed  Google Scholar 

  • Jin L, Li D, Alesi GN, Fan J, Kang HB, Lu Z, Boggon TJ, Jin P, Yi H, Wright ER, Duong D, Seyfried NT, Egnatchik R, DeBerardinis RJ, Magliocca KR, He C, Arellano ML, Khoury HJ, Shin DM, Khuri FR, Kang S (2015) Glutamate dehydrogenase 1 signals through antioxidant glutathione peroxidase 1 to regulate redox homeostasis and tumor growth. Cancer Cell 27:257–270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karaca M, Martin-Levilain J, Grimaldi M, Li L, Dizin E, Emre Y, Maechler P (2018) Liver glutamate dehydrogenase controls whole-body energy partitioning through amino acid-derived gluconeogenesis and ammonia homeostasis. Diabetes 67:1949–1961

    Article  CAS  PubMed  Google Scholar 

  • Karlstaedt A, Schiffer W, Taegtmeyer H (2018) Actionable metabolic pathways in heart failure and cancer-lessons from cancer cell metabolism. Front Cardiovasc Med 5:71

    Article  PubMed  PubMed Central  Google Scholar 

  • Karwi QG, Uddin GM, Ho KL, Lopaschuk GD (2018) Loss of metabolic flexibility in the failing heart. Front Cardiovasc Med 5:68

    Article  PubMed  PubMed Central  Google Scholar 

  • Kim B, Li J, Jang C, Arany Z (2017) Glutamine fuels proliferation but not migration of endothelial cells. EMBO J 36:2321–2333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC (2010) Myocardial fatty acid metabolism in health and disease. Physiol Rev 90:207–258

    Article  CAS  PubMed  Google Scholar 

  • Luczkowska K, Stekelenburg C, Sloan-Bena F, Ranza E, Gastaldi G, Schwitzgebel V, Maechler P (2020) Hyperinsulinism associated with GLUD1 mutation: allosteric regulation and functional characterization of p.G446V glutamate dehydrogenase. Hum Genomics 14:9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mastorodemos V, Zaganas I, Spanaki C, Bessa M, Plaitakis A (2005) Molecular basis of human glutamate dehydrogenase regulation under changing energy demands. J Neurosci Res 79:65–73

    Article  CAS  PubMed  Google Scholar 

  • Mathioudakis L, Bourbouli M, Daklada E, Kargatzi S, Michaelidou K, Zaganas I (2019) Localization of human glutamate dehydrogenases provides insights into their metabolic role and their involvement in disease processes. Neurochem Res 44:170–187

    Article  CAS  PubMed  Google Scholar 

  • Matsumoto K, Imagawa S, Obara N, Suzuki N, Takahashi S, Nagasawa T, Yamamoto M (2006) 2-Oxoglutarate downregulates expression of vascular endothelial growth factor and erythropoietin through decreasing hypoxia-inducible factor-1alpha and inhibits angiogenesis. J Cell Physiol 209:333–340

    Article  CAS  PubMed  Google Scholar 

  • McMullen JR, Sherwood MC, Tarnavski O, Zhang L, Dorfman AL, Shioi T, Izumo S (2004) Inhibition of mTOR signaling with rapamycin regresses established cardiac hypertrophy induced by pressure overload. Circulation 109:3050–3055

    Article  CAS  PubMed  Google Scholar 

  • Morishige S, Takahashi-Yanaga F, Ishikane S, Arioka M, Igawa K, Kuroo A, Tomooka K, Shiose A, Sasaguri T (2019) 2,5-Dimethylcelecoxib prevents isoprenaline-induced cardiomyocyte hypertrophy and cardiac fibroblast activation by inhibiting Akt-mediated GSK-3 phosphorylation. Biochem Pharmacol 168:82–90

    Article  CAS  PubMed  Google Scholar 

  • Osadchii OE (2007) Cardiac hypertrophy induced by sustained beta-adrenoreceptor activation: pathophysiological aspects. Heart Fail Rev 12:66–86

    Article  CAS  PubMed  Google Scholar 

  • Piao L, Fang YH, Parikh K, Ryan JJ, Toth PT, Archer SL (2013) Cardiac glutaminolysis: a maladaptive cancer metabolism pathway in the right ventricle in pulmonary hypertension. J Mol Med (berl) 91:1185–1197

    Article  CAS  Google Scholar 

  • Plaitakis A, Spanaki C, Mastorodemos V, Zaganas I (2003) Study of structure–function relationships in human glutamate dehydrogenases reveals novel molecular mechanisms for the regulation of the nerve tissue-specific (GLUD2) isoenzyme. Neurochem Int 43:401–410

    Article  CAS  PubMed  Google Scholar 

  • Rzeski W, Walczak K, Juszczak M, Langner E, Pozarowski P, Kandefer-Szerszen M, Pierzynowski SG (2012) Alpha-ketoglutarate (AKG) inhibits proliferation of colon adenocarcinoma cells in normoxic conditions. Scand J Gastroenterol 47:565–571

    Article  CAS  PubMed  Google Scholar 

  • Sciarretta S, Forte M, Frati G, Sadoshima J (2018) New insights into the role of mTOR signaling in the cardiovascular system. Circ Res 122:489–505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Son J, Lyssiotis CA, Ying H, Wang X, Hua S, Ligorio M, Perera RM, Ferrone CR, Mullarky E, Shyh-Chang N, Kang Y, Fleming JB, Bardeesy N, Asara JM, Haigis MC, DePinho RA, Cantley LC, Kimmelman AC (2013) Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496:101–105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stanley CA, Lieu YK, Hsu BY, Burlina AB, Greenberg CR, Hopwood NJ, Perlman K, Rich BH, Zammarchi E, Poncz M (1998) Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J Med 338:1352–1357

    Article  CAS  PubMed  Google Scholar 

  • Sun H, Olson KC, Gao C, Prosdocimo DA, Zhou M, Wang Z, Jeyaraj D, Youn JY, Ren S, Liu Y, Rau CD, Shah S, Ilkayeva O, Gui WJ, William NS, Wynn RM, Newgard CB, Cai H, Xiao X, Chuang DT, Schulze PC, Lynch C, Jain MK, Wang Y (2016) Catabolic defect of branched-chain amino acids promotes heart failure. Circulation 133:2038–2049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tham YK, Bernardo BC, Ooi JY, Weeks KL, McMullen JR (2015) Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets. Arch Toxicol 89:1401–1438

    Article  CAS  PubMed  Google Scholar 

  • van Bilsen M, Smeets PJ, Gilde AJ, van der Vusse GJ (2004) Metabolic remodelling of the failing heart: the cardiac burn-out syndrome? Cardiovasc Res 61:218–226

    Article  PubMed  Google Scholar 

  • Vanky FB, Hakanson E, Jorfeldt L, Svedjeholm R (2006) Does glutamate influence myocardial and peripheral tissue metabolism after aortic valve replacement for aortic stenosis? Clin Nutr 25:913–922

    Article  CAS  PubMed  Google Scholar 

  • Wang JW, Peng SY, Li JT, Wang Y, Zhang ZP, Cheng Y, Cheng DQ, Weng WH, Wu XS, Fei XZ, Quan ZW, Li JY, Li SG, Liu YB (2009) Identification of metastasis-associated proteins involved in gallbladder carcinoma metastasis by proteomic analysis and functional exploration of chloride intracellular channel 1. Cancer Lett 281:71–81

    Article  CAS  PubMed  Google Scholar 

  • Wang L, Yuan D, Zheng J, Wu X, Wang J, Liu X, He Y, Zhang C, Liu C, Wang T, Zhou Z (2019) Chikusetsu saponin IVa attenuates isoprenaline-induced myocardial fibrosis in mice through activation autophagy mediated by AMPK/mTOR/ULK1 signaling. Phytomedicine 58:152764

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Proud CG (2006) The mTOR pathway in the control of protein synthesis. Physiology (Bethesda) 21:362–369

    CAS  Google Scholar 

  • Wang Y, Deng P, Liu Y, Wu Y, Chen Y, Guo Y, Zhang S, Zheng X, Zhou L, Liu W, Li Q, Lin W, Qi X, Ou G, Wang C, Yuan Q (2020) Alpha-ketoglutarate ameliorates age-related osteoporosis via regulating histone methylations. Nat Commun 11:5596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Watanabe K, Nagao M, Toh R, Irino Y, Shinohara M, Iino T, Yoshikawa S, Tanaka H, Satomi-Kobayashi S, Ishida T, Hirata KI (2020) Critical role of glutamine metabolism in cardiomyocytes under oxidative stress. Biochem Biophys Res Commun 534:687–693

    Article  PubMed  Google Scholar 

  • Wu N, Yang M, Gaur U, Xu H, Yao Y, Li D (2016) Alpha-ketoglutarate: physiological functions and applications. Biomol Ther (Seoul) 24:1–8

    Article  CAS  Google Scholar 

  • Yang C, Ko B, Hensley CT, Jiang L, Wasti AT, Kim J, Sudderth J, Calvaruso MA, Lumata L, Mitsche M, Rutter J, Merritt ME, DeBerardinis RJ (2014) Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport. Mol Cell 56:414–424

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang H, Rudge DG, Koos JD, Vaidialingam B, Yang HJ, Pavletich NP (2013) mTOR kinase structure, mechanism and regulation. Nature 497:217–223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang Q, Liang X, Sun X, Zhang L, Fu X, Rogers CJ, Berim A, Zhang S, Wang S, Wang B, Foretz M, Viollet B, Gang DR, Rodgers BD, Zhu MJ, Du M (2016) AMPK/alpha-ketoglutarate axis dynamically mediates DNA demethylation in the prdm16 promoter and brown adipogenesis. Cell Metab 24:542–554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu SS, Cai Y, Ye JT, Pi RB, Chen SR, Liu PQ, Shen XY, Ji Y (2013) Sirtuin 6 protects cardiomyocytes from hypertrophy in vitro via inhibition of NF-kappaB-dependent transcriptional activity. Br J Pharmacol 168:117–128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zdzisinska B, Zurek A, Kandefer-Szerszen M (2017) Alpha-ketoglutarate as a molecule with pleiotropic activity: well-known and novel possibilities of therapeutic use. Arch Immunol Ther Exp (Warsz) 65:21–36

    Article  CAS  Google Scholar 

  • Zhou SG, Zhou SF, Huang HQ, Chen JW, Huang M, Liu PQ (2006) Proteomic analysis of hypertrophied myocardial protein patterns in renovascularly hypertensive and spontaneously hypertensive rats. J Proteome Res 5:2901–2908

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This research was supported by grants from the National Natural Science Foundation of China (82070268), the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01Y093), the National Engineering and Technology Research Center for New Drug Druggability Evaluation (Seed Program of Guangdong Province, 2017B090903004), and the Guangdong Basic and Applied Basic Research Foundation (2020A1515011512).

Author information

Authors and Affiliations

  1. School of Pharmaceutical Sciences, Sun Yat-Sen University, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangzhou, 510006, China

    Zhi-Rong Lin, Zhen-Zhen Li, Yan-Jun Cao, Wen-Jing Yu, Jian-Tao Ye & Pei-Qing Liu

Authors
  1. Zhi-Rong Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhen-Zhen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yan-Jun Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wen-Jing Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jian-Tao Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pei-Qing Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Liu PQ and Ye JT conceived and designed the research. Lin ZR conducted experiments. Li ZZ, Cao YJ, and Yu WJ contributed to new reagents or analytical tools. Lin ZR analyzed data. Lin ZR wrote the manuscript. All the authors read and approved the manuscript, and all data were generated in-house and that no paper mill was used.

Corresponding authors

Correspondence to Jian-Tao Ye or Pei-Qing Liu.

Ethics declarations

Ethics approval

The animal experiments protocol has been reviewed and approved by the Institutional Animal Care and Use Committee (IACUC), Sun Yat-Sen University (Approval No. SYSU-IACUC-2021–000282).

Consent to participate

All the authors consent for participation.

Consent for publication

All the authors consent for publication.

Competing interests

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1

(DOCX 154 KB)

Supplementary file2

(XLSX 12 KB)

Supplementary file3

(XLSX 35.5 MB)

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lin, ZR., Li, ZZ., Cao, YJ. et al. GDH promotes isoprenaline-induced cardiac hypertrophy by activating mTOR signaling via elevation of α-ketoglutarate level. Naunyn-Schmiedeberg's Arch Pharmacol 395, 1373–1385 (2022). https://doi.org/10.1007/s00210-022-02252-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-022-02252-0

Keywords

Search

Navigation