Skip to main content
SpringerLink
Log in

Necroptosis and RhoA/ROCK pathways: molecular targets of Nesfatin-1 in cardioprotection against myocardial ischemia/reperfusion injury in a rat model

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Nesfatin-1 as a new energy-regulating peptide has been known to display a pivotal role in modulation of cardiovascular functions and protection against ischemia/reperfusion injury. However, the detailed knowledge about molecular mechanisms underlying this protection has not been completely investigated yet. This study was designed to clarify the molecular mechanisms by which nesfatin-1 exert cardioprotection effects against myocardial ischemia–reperfusion (MI/R). Left anterior descending coronary artery (LAD) was ligated for 30 min to create a MI/R model in rats. MI/R rats were treated with three concentrations of nesfatin-1 (10, 15 and 20 µg/kg) then expression of necroptosis and necrosis mediators were measured by western blotting assay. Fibrosis, morphological damages, cardiac function, myocardial injury indictors and oxidative stress factors were evaluated as well. Induction of MI/R model resulted in cardiac dysfunction, oxidative stress, increased activity of RIPK1-RIPK3-MLKL axis and RhoA/ROCK pathway, extension of fibrosis and heart tissue damage. Highest tested concentration of nesfatin-1 markedly improved cardiac function. Moreover, it reduced oxidative stress, collagen deposition, and morphological damages, through inhibiting the expression of necroptosis mediators and also, necrosis including RIPK1, RIPK3, MLKL, ROCK1, and ROCK2 proteins. The lowest and middle tested concentrations of nesfatin-1 failed to exert protective effects against MI/R. These findings have shown that nesfatin-1 can exert cardioprotection against MI/R in a dose dependent manner by suppressing necroptosis via modulation of RIPK1-RIPK3-MLKL axis and RhoA/ROCK/RIP3 signaling pathway.

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

Data availability

The authors confirm that the data supporting the findings of this study are available within the article [and/or] its supplementary materials.

References

  1. Bokenberger K et al (2019) Work disability patterns before and after incident acute myocardial infarction and subsequent risk of common mental disorders: a Swedish cohort study. Sci Rep 9(1):1–9

    Article  CAS  Google Scholar 

  2. Poustchi F et al (2021) Combination therapy of killing diseases by injectable hydrogels: from concept to medical applications. Adv Healthcare Mater 10(3):2001571

    Article  CAS  Google Scholar 

  3. Barbaresko J, Rienks J, Nöthlings U (2018) Lifestyle indices and cardiovascular disease risk: a meta-analysis. Am J Prev Med 55(4):555–564

    Article  PubMed  Google Scholar 

  4. Martins I.J (2014) The global obesity epidemic is related to stroke, dementia and Alzheimer’s disease

  5. Martins IJ (2016) Anti-aging genes improve appetite regulation and reverse cell senescence and apoptosis in global populations. AAR 5(1):9–26

    Article  CAS  Google Scholar 

  6. Ceriello A (2005) Acute hyperglycaemia: a ‘new’risk factor during myocardial infarction. Eur Heart J 26(4):328–331

    Article  CAS  PubMed  Google Scholar 

  7. Rakhshan K et al (2019) ELABELA (ELA) peptide exerts cardioprotection against myocardial infarction by targeting oxidative stress and the improvement of heart function. Int J Pept Res Ther 25(2):613–621

    Article  CAS  Google Scholar 

  8. Mokhtari B et al (2020) Human amniotic membrane mesenchymal stem cells-conditioned medium attenuates myocardial ischemia-reperfusion injury in rats by targeting oxidative stress. IJBS 23(11):1453

    Google Scholar 

  9. Mao Y et al (2017) Nanoparticle-mediated delivery of pitavastatin to monocytes/macrophages inhibits left ventricular remodeling after acute myocardial infarction by inhibiting monocyte-mediated inflammation. Int Heart J 58(4):615–623

    Article  CAS  PubMed  Google Scholar 

  10. Amani H et al (2020) Microneedles for painless transdermal immunotherapeutic applications. J Control Release 330:185–217

    Article  PubMed  Google Scholar 

  11. Wang Z et al (2017) Fibroblast growth factor-1 released from a heparin coacervate improves cardiac function in a mouse myocardial infarction model. ACS Biomater Sci Eng 3(9):1988–1999

    Article  CAS  PubMed  Google Scholar 

  12. Johnson NR et al (2015) Coacervate delivery of growth factors combined with a degradable hydrogel preserves heart function after myocardial infarction. ACS Biomater Sci Eng 1(9):753–759

    Article  CAS  PubMed  Google Scholar 

  13. Amani H et al (2017) Antioxidant nanomaterials in advanced diagnoses and treatments of ischemia reperfusion injuries. J Mater Chem B 5(48):9452–9476

    Article  CAS  PubMed  Google Scholar 

  14. Koshinuma S et al (2014) Combination of necroptosis and apoptosis inhibition enhances cardioprotection against myocardial ischemia–reperfusion injury. J Anesth 28(2):235–241

    Article  PubMed  Google Scholar 

  15. Dorn GW (2009) Apoptotic and non-apoptotic programmed cardiomyocyte death in ventricular remodelling. Cardiovasc Res 81(3):465–473

    Article  CAS  PubMed  Google Scholar 

  16. McCaig WD et al (2018) Hyperglycemia potentiates a shift from apoptosis to RIP1-dependent necroptosis. Cell Death Discov 4(1):1–14

    Article  CAS  Google Scholar 

  17. Linkermann A et al (2012) Rip1 (receptor-interacting protein kinase 1) mediates necroptosis and contributes to renal ischemia/reperfusion injury. Kidney Int 81(8):751–761

    Article  CAS  PubMed  Google Scholar 

  18. Xu Y et al (2016) RIP3 induces ischemic neuronal DNA degradation and programmed necrosis in rat via AIF. Sci Rep 6:29362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cai Z et al (2014) Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Nat Cell Biol 16(1):55–65

    Article  CAS  Google Scholar 

  20. Cho Y et al (2009) Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137(6):1112–1123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhou T et al (2019) Identification of a novel class of RIP1/RIP3 dual inhibitors that impede cell death and inflammation in mouse abdominal aortic aneurysm models. Cell Death Dis 10(3):1–15

    Article  Google Scholar 

  22. Christofferson DE, Yuan J (2010) Necroptosis as an alternative form of programmed cell death. Curr Opin Cell Biol 22(2):263–268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhang T et al (2016) CaMKII is a RIP3 substrate mediating ischemia-and oxidative stress–induced myocardial necroptosis. Nat Med 22(2):175

    Article  PubMed  Google Scholar 

  24. Webster KA (2012) Mitochondrial membrane permeabilization and cell death during myocardial infarction: roles of calcium and reactive oxygen species. Future Cardiol 8(6):863–884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Dong M et al (2010) Rho-kinase inhibition: a novel therapeutic target for the treatment of cardiovascular diseases. Drug Discov Today 15(15–16):622–629

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Duan J-S et al (2019) Urotensin-# receptor antagonist SB-706375 protected isolated rat heart from ischaemia–reperfusion injury by attenuating myocardial necrosis via RhoA/ROCK/RIP3 signalling pathway. Inflammopharmacology 27(6):1309–1318

    Article  CAS  PubMed  Google Scholar 

  27. Mann DL, Bogaev R, Buckberg GD (2010) Cardiac remodelling and myocardial recovery: lost in translation? Eur J Heart Fail 12(8):789–796

    Article  PubMed  Google Scholar 

  28. Amani H et al (2018) Three-dimensional graphene foams: synthesis, properties, biocompatibility, biodegradability, and applications in tissue engineering. ACS Biomater Sci Eng 5(1):193–214

    Article  PubMed  Google Scholar 

  29. Feijóo-Bandín S et al (2013) Nesfatin-1 in human and murine cardiomyocytes: synthesis, secretion, and mobilization of GLUT-4. Endocrinology 154(12):4757–4767

    Article  PubMed  Google Scholar 

  30. Tekin T, Cicek B, Konyaligil N (2019) Regulatory peptide nesfatin-1 and its relationship with metabolic syndrome. Eurasian J Med 51(3):280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Angelone T et al (2013) Nesfatin-1 as a novel cardiac peptide: identification, functional characterization, and protection against ischemia/reperfusion injury. Cell Mol Life Sci 70(3):495–509

    Article  CAS  PubMed  Google Scholar 

  32. Naseroleslami M et al (2020) Nesfatin-1 attenuates injury in a rat model of myocardial infarction by targeting autophagy, inflammation, and apoptosis. Arch Physiol Biochem 1:1–9

    Article  Google Scholar 

  33. Reichert K et al (2017) Murine left anterior descending (LAD) coronary artery ligation: an improved and simplified model for myocardial infarction. JoVE 122:e55353

    Google Scholar 

  34. Samsamshariat SA, Samsamshariat ZA, Movahed M-R (2005) A novel method for safe and accurate left anterior descending coronary artery ligation for research in rats. Cardiovasc Revasc Med 6(3):121–123

    Article  PubMed  Google Scholar 

  35. Patten RD et al (1998) Ventricular remodeling in a mouse model of myocardial infarction. Am J Physiol Heart Circ Physiol 274(5):H1812–H1820

    Article  CAS  Google Scholar 

  36. Salto-Tellez M et al (2004) Myocardial infarction in the C57BL/6J mouse: a quantifiable and highly reproducible experimental model. Cardiovasc Pathol 13(2):91–97

    Article  PubMed  Google Scholar 

  37. Su T et al (2020) Cardiac stromal cell patch integrated with engineered microvessels improves recovery from myocardial infarction in rats and pigs. ACS Biomater Sci Eng 6(11):6309–6320

    Article  CAS  PubMed  Google Scholar 

  38. Köhler D et al (2020) Red blood cell-derived semaphorin 7A promotes thrombo-inflammation in myocardial ischemia-reperfusion injury through platelet GPIb. Nat Commun 11(1):1–12

    Article  Google Scholar 

  39. Saporito F et al (2018) In situ gelling scaffolds loaded with platelet growth factors to improve cardiomyocyte survival after ischemia. ACS Biomater Sci Eng 5(1):329–338

    Article  PubMed  Google Scholar 

  40. Amani H et al (2019) Controlling cell behavior through the design of biomaterial surfaces: a focus on surface modification techniques. Adv Mater Interfaces 6(13):1900572

    Article  Google Scholar 

  41. Xu Y, Chen F (2020) Antioxidant, anti-inflammatory and anti-apoptotic activities of nesfatin-1: a review. J Inflamm Res 13:607–617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Dai H et al (2013) Decreased plasma nesfatin-1 levels in patients with acute myocardial infarction. Peptides 46:167–171

    Article  CAS  PubMed  Google Scholar 

  43. Tasatargil A et al (2017) Cardioprotective effect of nesfatin-1 against isoproterenol-induced myocardial infarction in rats: role of the Akt/GSK-3β pathway. Peptides 95:1–9

    Article  CAS  PubMed  Google Scholar 

  44. Naseroleslami M, Aboutaleb N, Parivar K (2018) The effects of superparamagnetic iron oxide nanoparticles-labeled mesenchymal stem cells in the presence of a magnetic field on attenuation of injury after heart failure. Drug Deliv Transl Res 8(5):1214–1225

    Article  CAS  PubMed  Google Scholar 

  45. Amani H et al (2019) Would colloidal gold nanocarriers present an effective diagnosis or treatment for ischemic stroke? Int J Nanomed 14:8013

    Article  CAS  Google Scholar 

  46. Zhang H et al (2020) Necroptosis mediated by impaired autophagy flux contributes to adverse ventricular remodeling after myocardial infarction. Biochem Pharmacol 175:113915

    Article  CAS  PubMed  Google Scholar 

  47. Shulga N, Pastorino JG (2012) GRIM-19-mediated translocation of STAT3 to mitochondria is necessary for TNF-induced necroptosis. J Cell Sci 125(12):2995–3003

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Afousi AG et al (2019) Targeting necroptotic cell death pathway by high-intensity interval training (HIIT) decreases development of post-ischemic adverse remodelling after myocardial ischemia/reperfusion injury. Cell Commun Signal 13(2):255–267

    Article  Google Scholar 

  49. Zhang Q et al (2014) Atorvastatin treatment improves the effects of mesenchymal stem cell transplantation on acute myocardial infarction: The role of the RhoA/ROCK/ERK pathway. Int J Cardiol 176(3):670–679

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

Present work was funded by a research grant from Physiology Research Center in Iran University of Medical Sciences.

Author information

Authors and Affiliations

  1. Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran

    Masoomeh Sharifi, Fatemeh Ramezani, Yaser Azizi & Nahid Aboutaleb

  2. Department of Physiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran

    Masoomeh Sharifi, Yaser Azizi & Nahid Aboutaleb

  3. Department of Physiology, School of Paramedical Sciences, Dezful University of Medical Sciences, Dezful, Iran

    Donya Nazarinia

  4. Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran

    Nasim Naderi

Authors
  1. Masoomeh Sharifi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Donya Nazarinia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fatemeh Ramezani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yaser Azizi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nasim Naderi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nahid Aboutaleb
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization and Study design, N.A.; investigation and data collection, M.S., D.N., Y.A., N.N. and F.R; writing—original draft preparation, M.S.; writing—review and editing, M.S and N.A.

Corresponding author

Correspondence to Nahid Aboutaleb.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The animal use, experimental procedures, and care protocols were approved by School of Medicine Animal Care and Use Committee of Iran University of Medical Sciences. All protocols and animal operation rules were confirmed by the Animal Ethical Committee of Iran University of Medical Sciences.

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 1601 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sharifi, M., Nazarinia, D., Ramezani, F. et al. Necroptosis and RhoA/ROCK pathways: molecular targets of Nesfatin-1 in cardioprotection against myocardial ischemia/reperfusion injury in a rat model. Mol Biol Rep 48, 2507–2518 (2021). https://doi.org/10.1007/s11033-021-06289-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-021-06289-x

Keywords

Search

Navigation