Skip to main content
SpringerLink
Log in

Sestrin 2 attenuates neonatal rat cardiomyocyte hypertrophy induced by phenylephrine via inhibiting ERK1/2

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Cardiac hypertrophy is an adaptive response triggered by many physiological and pathological conditions and will lead to heart failure eventually. Sestrin 2, which is a stress-responsive protein, was reported to protect heart from ischemia reperfusion injury. However, the role of Sestrin 2 in cardiac hypertrophy remains unknown. In our present study, we aimed to explore the effects of Sestrin 2 on cardiomyocyte hypertrophy. We found that knockdown of Sestrin 2 protein aggravated cardiomyocyte hypertrophy induced by phenylephrine (PE), featured by increased hypertrophic marker ANP and cell surface area. During this process, ERK1/2 cascade was further activated, while p38, JNK1/2, and mTOR signaling pathways were not affected by downregulation of Sestrin 2. Moreover, overexpression of Sestrin 2 protein protected cardiomyocytes from PE-induced hypertrophy and ERK1/2 cascade was suppressed correspondingly. Importantly, pharmacological inhibition of ERK1/2 eliminated the exacerbated hypertrophic phenotype due to Sestrin 2 protein knockdown. In conclusion, we discovered that Sestrin 2 protected against cardiomyocyte hypertrophy induced by PE via inhibiting ERK1/2 signaling.

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

Similar content being viewed by others

Abbreviations

PE:

Phenylephrine

Hi 95:

Hypoxia-inducible gene 95

MAPK:

Mitogen-activated protein kinase

ERK1/2:

Extracellular signal-regulated protein kinase

JNK1/2:

c-Jun N-terminal protein kinase

mTOR:

Mammalian target of rapamycin

mTORC1:

mTOR complex 1

mTORC2:

mTOR complex 2

References

  1. Pillai VB, Samant S, Sundaresan NR, Raghuraman H, Kim G, Bonner MY, Arbiser JL, Walker DI, Jones DP, Gius D, Gupta MP (2015) Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial Sirt 3. Nat Commun 6:6656. doi:10.1038/ncomms7656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lee JH, Budanov AV, Karin M (2013) Sestrins orchestrate cellular metabolism to attenuate aging. Cell Metab 18:792–801. doi:10.1016/j.cmet.2013.08.018

    Article  CAS  PubMed  Google Scholar 

  3. Rhee SG, Bae SH (2015) The antioxidant function of Sestrins is mediated by promotion of autophagic degradation of Keap1 and Nrf2 activation and by inhibition of mTORC1. Free Radic Biol Med 88(Part B):205–211. doi:10.1016/j.freeradbiomed.2015.06.007

    Article  CAS  PubMed  Google Scholar 

  4. Peng M, Yin N, Li MO (2014) Sestrins function as guanine nucleotide dissociation inhibitors for Rag GTPases to control mTORC1 signaling. Cell 159:122–133. doi:10.1016/j.cell.2014.08.038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Budanov AV, Karin M (2008) P53 target genes Sestrin 1 and Sestrin 2 connect genotoxic stress and mTOR signaling. Cell 134:451–460. doi:10.1016/j.cell.2008.06.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Saxton RA, Knockenhauer KE, Wolfson RL, Chantranupong L, Pacold ME, Wang T, Schwartz TU, Sabatini DM (2016) Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway. Science 351:53–58. doi:10.1126/science.aad2087

    Article  CAS  PubMed  Google Scholar 

  7. Yang Y, Cuevas S, Yang S, Villar VA, Escano C, Asico L, Yu P, Jiang X, Weinman EJ, Armando I, Jose PA (2014) Sestrin 2 decreases renal oxidative stress, lowers blood pressure, and mediates dopamine D2 receptor-induced inhibition of reactive oxygen species production. Hypertension 64:825–832. doi:10.1161/HYPERTENSIONAHA.114.03840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kim H, An S, Ro SH, Teixeira F, Park GJ, Kim C, Cho CS, Kim JS Jakob U, Lee JH, Cho US (2015) Janus-faced Sestrin2 controls ROS and mTOR signalling through two separate functional domains. Nat Commun 6:10025. doi:10.1038/ncomms10025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Budanov AV, Sablina AA, Feinstein E, Koonin EV, Chumakov PM (2004) Regeneration of peroxiredoxins by p53-regulated Sestrins, homologs of bacterial AphD. Science 304:596–600. doi:10.1126/science.1095569

    Article  CAS  PubMed  Google Scholar 

  10. Bae SH, Sung SH, Oh SY, Lim JM, Lee SK, Park YN, Lee HE, Kang D, Rhee SG (2013) Sestrins activate Nrf2 by promoting p62-dependent autophagic degradation of Keap1 and prevent oxidative liver damage. Cell Metab 17:73–84. doi:10.1016/j.cmet.2012.12.002

    Article  CAS  PubMed  Google Scholar 

  11. Kallenborn-Gerhardt W, Lu R, Syhr KM, Heidler J, von Melchner H, Geisslinger G, Bangsow T, Schmidtko A (2013) Antioxidant activity of Sestrin 2 controls neuropathic pain after peripheral nerve injury. Antioxid Redox Signal 19:2013–2023. doi:10.1089/ars.2012.4958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Parmigiani A, Nourbakhsh A, Ding B, Wang W, Kim YC, Akopiants K, Guan KL, Karin M, Budanov AV (2014) Sestrins inhibit mTORC1 kinase activation through the GATOR complex. Cell Rep 9:1281–1291. doi:10.1016/j.celrep.2014.10.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hou YS, Guan JJ, Xu HD, Wu F, Sheng R, Qin ZH (2015) Sestrin2 protects dopaminergic cells against rotenone toxicity through AMPK-dependent autophagy activation. Mol Cell Biol 35:2740–2751. doi:10.1128/MCB.00285-15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Morrison A, Chen L, Wang J, Zhang M, Yang H, Ma Y, Budanov A, Lee JH, Karin M, Li J (2015) Sestrin 2 promotes LKB1-mediated AMPK activation in the ischemic heart. FASEB J 29:408–417. doi:10.1096/fj.14-258814

    Article  CAS  PubMed  Google Scholar 

  15. Zeng YC, Chi F, Xing R, Zeng J, Gao S, Chen JJ, Wang HM, Duan QY, Sun YN, Niu N, Tang MY, Wu R (2016) Sestrin2 protects the myocardium against radiation-induced damage. Radiat Environ Biophys 55:195–202. doi:10.1007/s00411-016-0643-8

    Article  CAS  PubMed  Google Scholar 

  16. Chang L, Karin M (2001) Mammalian MAP kinase signaling cascades. Nature 410:37–40. doi:10.1038/35065000

    Article  CAS  PubMed  Google Scholar 

  17. Javadov S, Jang S, Agostini B (2014) Crosstalk between mitogen-activated protein kinases and mitochondria in cardiac diseases: therapeutic perspectives. Pharmacol Ther 144:202–225. doi:10.1016/j.pharmthera

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lu J, Bian ZY, Zhang R, Zhang Y, Liu C, Yan L, Zhang SM, Jiang DS, Wei X, Zhu XH, Chen M, Wang AB, Chen Y, Yang Q, Liu PP, Li H (2013) Interferon regulatory factor 3 is a negative regulator of pathological cardiac hypertrophy. Basic Res Cardiol 108:326. doi:10.1007/s00395-012-0326-9

    Article  PubMed  Google Scholar 

  19. Muslin AJ (2008) MAPK signaling in cardiovascular health and disease: molecular mechanisms and therapeutic targets. Clin Sci 115:203–218. doi:10.1042/CS20070430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Barry SP, Davidson SM, Townsend PA (2008) Molecular regulation of cardiac hypertrophy. Int J Biochem Cell Biol 40:2023–2039. doi:10.1016/j.biocel.2008.02.020

    Article  CAS  PubMed  Google Scholar 

  21. Glennon PE, Kaddoura S, Sale EM, Sale JG, Fuller SJ, Sugden PH (1996) Depletion of mitogen-activated protein kinase using an antisense oligodeoxynucleotide approach downregulates the phenylephrine-induced hypertrophic response in rat cardiac myocytes. Circ Res 78:954–961. doi:10.1161/01.RES.78.6.954

    Article  CAS  PubMed  Google Scholar 

  22. Bueno OF, De Windt LJ, Tymitz KM, Witt SA, Kimball TR, Klevitsky R, Hewett TE, Jones SP, Lefer DJ, Peng CF, Kitsis RN, Molkentin JD (2000) The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice. EMBO J 19:6341–6350. doi:10.1093/emboj/19.23.6341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yue TL, Gu JL, Wang C, Reith AD, Lee JC, Mirabile RC, Kreutz R, Wang Y, Maleeff B, Parsons AA, Ohlstein EH (2000) Extracellular signal-regulated kinase plays an essential role in hypertrophic agonists, endothelin-1 and phenylephrine-induced cardiomyocyte hypertrophy. J Biol Chem 275:37895–37901. doi:10.1074/jbc.M007037200

    Article  CAS  PubMed  Google Scholar 

  24. Liang Q, Molkentin JD (2003) Redefining roles of p38 and JNK signaling in cardiac hypertrophy: dichotomy between cultured myocytes and animal models. J Mol Cell Cardiol 35:1385–1394. doi:10.1016/j.yjmcc.2003.10.001

    Article  CAS  PubMed  Google Scholar 

  25. Volkers M, Toko H, Doroudgar S, Din S, Quijada P, Joyo AY, Ornrlas L, Joyo E, Thyerauf DJ, Konstandin MH, Gude N, Glembotski CC, Sussman MA (2013) Pathological hypertrophy amelioration by PRAS40-mediated inhibition of mTORC1. Proc Natl Acad Sci USA 110:12661–12666. doi:10.1073/pnas.1301455110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang RH, He JP, Su ML, Luo J, Xu M, Du XD, Chen HZ, Wang WJ, Wang Y, Zhang N, Zhao BX, Zhao WX, Shan ZG, Han J, Chang C, Wu Q (2013) The orphan receptor TR3 participates in angiotensin II-induced cardiac hypertrophy by controlling mTOR signaling. EMBO Mol Med 5:137–148. doi:10.1002/emmm.201201369

    Article  CAS  PubMed  Google Scholar 

  27. Malhowski AJ, Hira H, Bashiruddin S, Warburton R, Goto J, Robert B, Kwiatkowski DJ, Finalay GA (2011) Smooth muscle protein-22-mediated deletion of Tsc1 results in cardiac hypertrophy that is mTORC1-mediated and reversed by rapamycin. Hum Mol Genet 20:1290–1305. doi:10.1093/hmg/ddq570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Pettazzoni P, Viale A, Shah P, Carugo A, Ying H, Wang H, Genovese G, Seth S, Minelli R, Green T, Huang-Hobbs E, Corti D, Sanchez N, Nezi L, Marchesini M, Kapoor A, Yao W, Francesco ME, Petrocchi A, Deem AK, Scott K, Colla S, Mills GB, Fleming JB, Heffernan TP, Jones P, Toniatti C, DePinho RA, Draetta GF (2011) Genetic events that limit the efficacy of MEK and RTK inhibitor therapies in a mouse model of KRAS-driven pancreatic cancer. Cancer Res 75:1091–1101. doi:10.1158/0008-5472.CAN-14-1854

    Article  Google Scholar 

  29. Turke AB, Song Y, Costa C, Cook R, Arteaga CL, Asara JM, Engelman JA (2012) MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors. Cancer Res 72:3228–3237. doi:10.1158/0008-5472.CAN-11-3747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, Egia A, Sasaki AT, Thomas G, Kozma SC, Papa A, Nardella C, Cantley LC, Baselga J, Pandolfi PP (2008) Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Investig 118:3065–3074. doi:10.1172/JCI34739

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Melemedjian OK, Khoutorsky A, Sorge RE, Yan J, Asiedu MN, Valdez A, Ghosh S, Dussor G, Mogil JS, Sonenberg N, Price TJ (2013) mTORC1 inhibition induces pain via IRS-1-dependent feedback activation of ERK. Pain 154:1080–1091. doi:10.1016/j.pain.2013.03.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work is supported by the National Natural Science Foundation of China (Nos. 81200173, 81370338, 81470511 and 81570354), Guangdong Natural Science Foundation (Nos. S2013020012578 and 2015A030313111), the Ph.D. Programs Foundation of Ministry of Education of China (No. 20120171110074), and Guangdong Scientific Program Foundation (No. 2012B031800300).

Author information

Authors and Affiliations

  1. Department of Cardiology, Heart Center, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan Road 2, Guangzhou, 510080, China

    Bin Dong, Ruicong Xue, Yu Sun, Yugang Dong & Chen Liu

  2. Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, 510080, China

    Bin Dong, Ruicong Xue, Yu Sun, Yugang Dong & Chen Liu

Authors
  1. Bin Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ruicong Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yu Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yugang Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chen Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yugang Dong or Chen Liu.

Ethics declarations

Conflict of interest

None declared.

Ethical approval

Our ethical approval number is “[2014]A-176” (approved by ethical committee of Sun Yat-sen University). All of the experimental protocols complied with the guide for the care and use of laboratory animals published by the Animal Care and Use Committees of the Sun Yat-Sen University and guide for the care and use of laboratory animals published by the US National Institutes of Health.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dong, B., Xue, R., Sun, Y. et al. Sestrin 2 attenuates neonatal rat cardiomyocyte hypertrophy induced by phenylephrine via inhibiting ERK1/2. Mol Cell Biochem 433, 113–123 (2017). https://doi.org/10.1007/s11010-017-3020-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-017-3020-2

Keywords

Search

Navigation