Skip to main content

Advertisement

SpringerLink
Log in

Exendin-4 Ameliorates Cardiac Remodeling in Experimentally Induced Myocardial Infarction in Rats by Inhibiting PARP1/NF-κB Axis in A SIRT1-Dependent Mechanism

  • Published:
Cardiovascular Toxicology Aims and scope Submit manuscript

Abstract

Sirt1 is a potent inhibitor of both poly(ADP-ribose) polymerases1 (PARP1) and NF-kB. This study investigated the cardioprotective effect of exendin-4 on cardiac function and remodeling in rats after an expreimentally-induced myocardial infarction (MI) and explored if this protection involves SIRT1/PARP1 axis. Rats were divided into five groups (n = 10/each): sham, sham + exendin-4 (25 nmol/kg/day i.p.), MI (induced by LAD occlusion), MI + exendin-4, and sham + exendin-4 + EX527 (5 mg/2×/week) (a SIRT1 inhibitor). All treatments were given for 6 weeks post the induction of MI. In sham-operated and MI-induced rats, exendin-4 significantly upregulated Bcl-2 levels, enhanced activity, mRNA, and levels of SIRT1, inhibited activity, mRNA, and levels of PARP1, and reduced ROS generation and PARP1 acetylation. In MI-treated rats, these effects were associated with improved cardiac architectures and LV function, reduced collagen deposition, and reduced mRNA and total levels of TNF-α and IL-6, as well as, the activation of NF-κB p65. In addition, exendin-4 inhibited the interaction of PARP1 with p300, TGF-β1, Smad3, and NF-κB p65 and signficantly reduced mRNA and protein levels of collagen I/III and protein levels of MMP2/9. In conclusion, exendin-4 is a potent cardioprotective agent that prevents post-MI inflammation and cardiac remodeling by activating SIRT1-induced inhibition of PARP1.

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
Fig. 7

Similar content being viewed by others

References

  1. Suthahar, N., Meijers, W. C., Silljé, H. H., & de Boer, R. A. (2017). From inflammation to fibrosis—Molecular and cellular mechanisms of myocardial tissue remodelling and perspectives on differential treatment opportunities. Current Heart Failure Reports,14, 235–250.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Schirone, L., Forte, M., Palmerio, S., Yee, D., Nocella, C., Angelini, F., et al. (2017). A review of the molecular mechanisms underlying the development and progression of cardiac remodeling. Oxidative Medicine and Cellular Longevity,2017, 3920195.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Hill, J. A., & Olson, E. N. (2008). Cardiac plasticity. New England Journal of Medicine,358, 1370–1380.

    Article  CAS  Google Scholar 

  4. Ohtani, T., Mohammed, S. F., Yamamoto, K., Dunlay, S. M., Weston, S. A., Sakata, Y., et al. (2012). Diastolic stiffness as assessed by diastolic wall strain is associated with adverse remodelling and poor outcomes in heart failure with preserved ejection fraction. European Heart Journal,33, 1742–1749.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Burchfield, J. S., Xie, M., & Hill, J. A. (2013). Pathological ventricular remodeling: Mechanisms: Part 1 of 2. Circulation,128, 388–400.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Pacher, P., Liaudet, L., Bai, P., Virag, L., Mabley, J., Hasko, G., et al. (2002). Activation of poly (ADP-ribose) polymerase contributes to development of doxorubicin-induced heart failure. Journal of Pharmacology and Experimental Therapeutics,300, 862–867.

    Article  CAS  Google Scholar 

  7. Szabo, C. (2005). Pharmacological inhibition of poly (ADP-ribose) polymerase in cardiovascular disorders: Future directions. Current Vascular Pharmacology,3, 301–303.

    Article  CAS  PubMed  Google Scholar 

  8. Wang, J., Hao, L., Wang, Y., Qin, W., Wang, X., Zhao, T., et al. (2015). Inhibition of poly (ADP-ribose) polymerase and inducible nitric oxide synthase protects against ischemic myocardial damage by reduction of apoptosis. Molecular Medicine Reports,11, 1768–1776.

    Article  CAS  PubMed  Google Scholar 

  9. Sun, S., Hu, Y., Zheng, Q., Guo, Z., Sun, D., Chen, S., et al. (2019). Poly (ADP-ribose) polymerase 1 induces cardiac fibrosis by mediating mammalian target of rapamycin activity. Journal of Cellular Biochemistry,120, 4813–4826.

    Article  CAS  PubMed  Google Scholar 

  10. Ling, X. X., Liu, J. X., Lin, Y., Du, Y. J., Chen, S. Q., Chen, J. L., et al. (2016). Poly(ADP-ribosyl)ation of apoptosis antagonizing transcription factor involved in hydroquinone-induced DNA damage response. Biomedical and Environmental Sciences,29, 80–84.

    PubMed  CAS  Google Scholar 

  11. d’Amours, D., Desnoyers, S., d’Silva, I., & Poirier, G. G. (1999). Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions. Biochemical Journal,342, 249.

    Article  PubMed Central  Google Scholar 

  12. Rajamohan, S. B., Pillai, V. B., Gupta, M., Sundaresan, N. R., Birukov, K. G., Samant, S., et al. (2009). SIRT1 promotes cell survival under stress by deacetylation-dependent deactivation of poly (ADP-ribose) polymerase 1. Molecular and Cellular Biology,29, 4116–4129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Szabo, C., Zingarelli, B., O'Connor, M., & Salzman, A. L. (1996). DNA strand breakage, activation of poly (ADP-ribose) synthetase, and cellular energy depletion are involved in the cytotoxicity of macrophages and smooth muscle cells exposed to peroxynitrite. Proceedings of the National Academy of Sciences,93, 1753–1758.

    Article  CAS  Google Scholar 

  14. Hassa, P., & Hottiger, M. (2002). The functional role of poly (ADP-ribose) polymerase 1 as novel coactivator of NF-κB in inflammatory disorders. Cellular and Molecular Life Sciences,59, 1534–1553.

    Article  CAS  PubMed  Google Scholar 

  15. Yao, L., Huang, K., Huang, D., Wang, J., Guo, H., & Liao, Y. (2008). Acute myocardial infarction induced increases in plasma tumor necrosis factor-α and interleukin-10 are associated with the activation of poly (ADP-ribose) polymerase of circulating mononuclear cell. International Journal of Cardiology,123, 366–368.

    Article  PubMed  Google Scholar 

  16. Halmosi, R., Deres, L., Gal, R., Eros, K., Sumegi, B., & Toth, K. (2016). PARP inhibition and postinfarction myocardial remodeling. International Journal of Cardiology,217, S52–S59.

    Article  PubMed  Google Scholar 

  17. Jia, G., Zao, M., & Liu, X. (2017). Protective effect of diethylcarbamazine inhibits NF-κB activation in isoproterenol-induced acute myocardial infarction rat model through the PARP pathway. Molecular Medicine Reports,16, 1596–1602.

    Article  CAS  PubMed  Google Scholar 

  18. Hans, C. P., Zerfaoui, M., Naura, A. S., Catling, A., & Boulares, A. H. (2008). Differential effects of PARP inhibition on vascular cell survival and ACAT-1 expression favouring atherosclerotic plaque stability. Cardiovascular Research,78, 429–439.

    Article  CAS  PubMed  Google Scholar 

  19. Eid, R. A., Zaki, M. S. A., Al-Shraim, M., Eleawa, S. M., El-kott, A. F., Al-Hashem, F. H., et al. (2018). Subacute ghrelin administration inhibits apoptosis and improves ultrastructural abnormalities in remote myocardium post-myocardial infarction. Biomedicine & Pharmacotherapy,101, 920–928.

    Article  CAS  Google Scholar 

  20. Drucker, D. J. (2016). The cardiovascular biology of glucagon-like peptide-1. Cell Metabolism,24, 15–30.

    Article  CAS  PubMed  Google Scholar 

  21. Timmers, L., Henriques, J. P., de Kleijn, D. P., DeVries, J. H., Kemperman, H., Steendijk, P., et al. (2009). Exenatide reduces infarct size and improves cardiac function in a porcine model of ischemia and reperfusion injury. Journal of the American College of Cardiology,53, 501–510.

    Article  CAS  PubMed  Google Scholar 

  22. Woo, J. S., Kim, W., Ha, S. J., Kim, J. B., Kim, S.-J., Kim, W.-S., et al. (2013). Cardioprotective effects of exenatide in patients with ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention: Results of exenatide myocardial protection in revascularization study. Arteriosclerosis, Thrombosis, and Vascular Biology,33, 2252–2260.

    Article  CAS  PubMed  Google Scholar 

  23. Noyan-Ashraf, M. H., Shikatani, E. A., Schuiki, I., Mukovozov, I., Wu, J., Li, R.-K., et al. (2013). A glucagon-like peptide-1 analog reverses the molecular pathology and cardiac dysfunction of a mouse model of obesity. Circulation,127, 74–85.

    Article  CAS  PubMed  Google Scholar 

  24. Aravindhan, K., Bao, W., Harpel, M. R., Willette, R. N., Lepore, J. J., & Jucker, B. M. (2015). Cardioprotection resulting from glucagon-like peptide-1 administration involves shifting metabolic substrate utilization to increase energy efficiency in the rat heart. PLoS ONE,10, e0130894.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Li, J., Zheng, J., Wang, S., Lau, H. K., Fathi, A., & Wang, Q. (2017). Cardiovascular benefits of native GLP-1 and its metabolites: An indicator for GLP-1-therapy strategies. Frontiers in Physiology,8, 15.

    PubMed  PubMed Central  Google Scholar 

  26. Robinson, E., Cassidy, R. S., Tate, M., Zhao, Y., Lockhart, S., Calderwood, D., et al. (2015). Exendin-4 protects against post-myocardial infarction remodelling via specific actions on inflammation and the extracellular matrix. Basic Research in Cardiology,110, 20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Tate, M., Robinson, E., Green, B. D., McDermott, B. J., & Grieve, D. J. (2016). Exendin-4 attenuates adverse cardiac remodelling in streptozocin-induced diabetes via specific actions on infiltrating macrophages. Basic Research in Cardiology,111, 1.

    Article  CAS  PubMed  Google Scholar 

  28. Hsu, C.-P., Zhai, P., Yamamoto, T., Maejima, Y., Matsushima, S., Hariharan, N., et al. (2010). Silent information regulator 1 protects the heart from ischemia/reperfusion. Circulation,122, 2170–2182.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Mao, S., Chen, P., Li, T., Guo, L., & Zhang, M. (2018). Tongguan capsule mitigates post-myocardial infarction remodeling by promoting autophagy and inhibiting apoptosis: Role of Sirt1. Frontiers in Physiology,9, 589.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Minematsu, T., Huang, L., Ibuki, A., Nakagami, G., Akase, T., Sugama, J., et al. (2012). Altered expression of matrix metalloproteinases and their tissue inhibitors in matured rat adipocytes in vitro. Biological Research for Nursing,14, 242–249.

    Article  CAS  PubMed  Google Scholar 

  31. Bai, J., Zhang, N., Hua, Y., Wang, B., Ling, L., Ferro, A., et al. (2013). Metformin inhibits angiotensin II-induced differentiation of cardiac fibroblasts into myofibroblasts. PLoS ONE,8, e72120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sun, L., Liu, C., Xu, X., Ying, Z., Maiseyeu, A., Wang, A., et al. (2013). Ambient fine particulate matter and ozone exposures induce inflammation in epicardial and perirenal adipose tissues in rats fed a high fructose diet. Particle and Fibre Toxicology,10, 43.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Seo, S., Lee, M.-S., Chang, E., Shin, Y., Oh, S., Kim, I.-H., et al. (2015). Rutin increases muscle mitochondrial biogenesis with AMPK activation in high-fat diet-induced obese rats. Nutrients,7, 8152–8169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yan, N., Liu, Y., Liu, S., Cao, S., Wang, F., Wang, Z., et al. (2016). Fluoride-induced neuron apoptosis and expressions of inflammatory factors by activating microglia in rat brain. Molecular Neurobiology,53, 4449–4460.

    Article  CAS  PubMed  Google Scholar 

  35. Fusegawa, Y., Hashizume, H., Okumura, T., Deguchi, Y., Shina, Y., Ikari, Y., et al. (2006). Hypertensive patients with carotid artery plaque exhibit increased platelet aggregability. Thrombosis Research,117, 615–622.

    Article  CAS  PubMed  Google Scholar 

  36. Zhao, H., Zhang, J., & Hong, G. (2018). Minocycline improves cardiac function after myocardial infarction in rats by inhibiting activation of PARP-1. Biomedicine & Pharmacotherapy,97, 1119–1124.

    Article  CAS  Google Scholar 

  37. Harvey, A. P., & Grieve, D. J. (2014). Reactive oxygen species (ROS) signaling in cardiac remodeling and failure. In I. Laher (Ed.), Systems biology of free radicals and antioxidants (pp. 951–992). Berlin: Springer.

    Chapter  Google Scholar 

  38. Bai, S., He, C., Zhang, K., Ding, X., Zeng, Q., Wang, J., et al. (2019). Effects of dietary inclusion of Radix Bupleuri and Radix Astragali extracts on the performance, intestinal inflammatory cytokines expression, and hepatic antioxidant capacity in broilers exposed to high temperature. Animal Feed Science and Technology,259, 114288.

    Article  CAS  Google Scholar 

  39. Shou, Y., Li, N., Li, L., Borowitz, J. L., & Isom, G. E. (2002). NF-κB-mediated up-regulation of Bcl-XS and Bax contributes to cytochrome c release in cyanide-induced apoptosis. Journal of Neurochemistry,81, 842–852.

    Article  CAS  PubMed  Google Scholar 

  40. Gupta, S., Afaq, F., & Mukhtar, H. (2002). Involvement of nuclear factor-kappa B, Bax and Bcl-2 in induction of cell cycle arrest and apoptosis by apigenin in human prostate carcinoma cells. Oncogene,21, 3727.

    Article  CAS  PubMed  Google Scholar 

  41. Matsuzawa, A., Nishitoh, H., Tobiume, K., Takeda, K., & Ichijo, H. (2002). Physiological roles of ASK1-mediated signal transduction in oxidative stress-and endoplasmic reticulum stress-induced apoptosis: Advanced findings from ASK1 knockout mice. Antioxidants and Redox Signaling,4, 415–425.

    Article  CAS  PubMed  Google Scholar 

  42. Vaziri, H., Dessain, S. K., Eaton, E. N., Imai, S.-I., Frye, R. A., Pandita, T. K., et al. (2001). hSIR2SIRT1 functions as an NAD-dependent p53 deacetylase. Cell,107, 149–159.

    Article  CAS  PubMed  Google Scholar 

  43. Chong, A.-Y., & Lip, G. Y. (2002). Hormone replacement therapy and cardiovascular risk. Treatments in Endocrinology,1, 95–103.

    Article  PubMed  Google Scholar 

  44. Kim, H. J., Joe, Y., Yu, J. K., Chen, Y., Jeong, S. O., Mani, N., et al. (2015). Carbon monoxide protects against hepatic ischemia/reperfusion injury by modulating the miR-34a/SIRT1 pathway. Biochimica et Biophysica Acta,1852, 1550–1559.

    Article  CAS  PubMed  Google Scholar 

  45. Di, W., Lv, J., Jiang, S., Lu, C., Yang, Z., Ma, Z., et al. (2018). PGC-1: The energetic regulator in cardiac metabolism. Current Issues in Molecular Biology,28, 29–46.

    Article  PubMed  Google Scholar 

  46. Fredj, S., Bescond, J., Louault, C., Delwail, A., & LecronPotreau, J. C. D. (2005). Role of interleukin-6 in cardiomyocyte/cardiac fibroblast interactions during myocyte hypertrophy and fibroblast proliferation. Journal of Cellular Physiology,204, 428–436.

    Article  CAS  PubMed  Google Scholar 

  47. Pellman, J., Zhang, J., & Sheikh, F. (2016). Myocyte-fibroblast communication in cardiac fibrosis and arrhythmias: Mechanisms and model systems. Journal of Molecular and Cellular Cardiology,94, 22–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bujak, M., & Frangogiannis, N. G. (2007). The role of TGF-β signaling in myocardial infarction and cardiac remodeling. Cardiovascular Research,74, 184–195.

    Article  CAS  PubMed  Google Scholar 

  49. Gong, D., Shi, W., Yi, S.-J., Chen, H., Groffen, J., & Heisterkamp, N. (2012). TGFβ signaling plays a critical role in promoting alternative macrophage activation. BMC Immunology,13, 31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. DeLeon-Pennell, K. Y., Meschiari, C. A., Jung, M., & Lindsey, M. L. (2017). Matrix metalloproteinases in myocardial infarction and heart failure. Progress in Molecular Biology and Translational Science,147, 75–100.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Kawano, S., Kubota, T., Monden, Y., Tsutsumi, T., Inoue, T., Kawamura, N., et al. (2006). Blockade of NF-κB improves cardiac function and survival after myocardial infarction. American Journal of Physiology-Heart and Circulatory Physiology,291, H1337–H1344.

    Article  CAS  PubMed  Google Scholar 

  52. Guo, C., Huang, T., Chen, A., Chen, X., Wang, L., Shen, F., et al. (2016). Glucagon-like peptide 1 improves insulin resistance in vitro through anti-inflammation of macrophages. Brazilian Journal of Medical and Biological Research,49(12), e5826.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Iwaya, C., Nomiyama, T., Komatsu, S., Kawanami, T., Tsutsumi, Y., Hamaguchi, Y., et al. (2017). Exendin-4, a glucagonlike peptide-1 receptor agonist, attenuates breast cancer growth by inhibiting NF-κ B activation. Endocrinology,158, 4218–4232.

    Article  CAS  PubMed  Google Scholar 

  54. De Flora, A., Zocchi, E., Guida, L., Franco, L., & Bruzzone, S. (2004). Autocrine and paracrine calcium signaling by the CD38/NAD+/cyclic ADP-ribose system. Annals of the New York Academy of Sciences,1028, 176–191.

    PubMed  Google Scholar 

  55. Kauppinen, T. M., Gan, L., & Swanson, R. A. (2013). Poly(ADP-ribose) polymerase-1-induced NAD+ depletion promotes nuclear factor-κB transcriptional activity by preventing p65 de-acetylation. Biochimica et Biophysica Acta,1833, 1985–1991.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors extend their appreciation to the Deanship of Scientific Research at King Khalid University for funding this work through research groups program under Grant Number (R.G.P. 1/40/40).

Funding

This work is fully funded by Deanship of Scientific Research at King Khalid University for funding this work through research groups program under Grant Number (R.G.P. 1/40/40).

Author information

Authors and Affiliations

  1. Department of Pathology, College of Medicine, King Khalid University, Abha, Saudi Arabia

    Refaat A. Eid & Fahmy El-Sayed

  2. Department of Physiology, College of Medicine, Umm Al-Qura University, Mekkah, Saudi Arabia

    Samah A. Alharbi

  3. Department of Biology, College of Science, King Khalid University, P.O. 641, Abha, 61421, Saudi Arabia

    Attalla Farag El-kott

  4. Department of Zoology, Faculty of Science, Damanhour University, Damanhour, Egypt

    Attalla Farag El-kott

  5. Department of Applied Medical Sciences, College of Health Sciences, PAAET, Shuwaikh, Kuwait

    Samy M. Eleawa

  6. Department of Anatomy, College of Medicine, King Khalid University, P.O. 641, Abha, 61421, Saudi Arabia

    Mohamed Samir Ahmed Zaki

  7. Department of Histology, Faculty of Medicine, Zagazig University, Zagazig, Egypt

    Mohamed Samir Ahmed Zaki

  8. Biology Department, Physiology Section, Faculty of Science, Zagazig University, Zagazig, Egypt

    Muhammad Alaa Eldeen

  9. Department of Basic Medical Sciences/College of Medicine/King Saud bin, Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia

    Hussain Aldera

  10. Department of Medical Laboratory Sciences, The Hashemite University, Zarqa, Jordan

    Abd Al-Rahman Salem Al-Shudiefat

Authors
  1. Refaat A. Eid
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Samah A. Alharbi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Attalla Farag El-kott
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Samy M. Eleawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mohamed Samir Ahmed Zaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fahmy El-Sayed
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Muhammad Alaa Eldeen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hussain Aldera
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Abd Al-Rahman Salem Al-Shudiefat
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

RE obtained the fund. RE, HAD, SA , AAA, and SME designed the experimental procedure and drafted the proposal. MAE, RE and FE established the animal model and collected samples and blood. RE, AFE, MSAZ, MAS, FE, MAE performed the biochemical analysis and histopathology and electron microscopy studies. RE, AAA, SME HAD, and SA drafted the final version of the manuscript.

Corresponding author

Correspondence to Refaat A. Eid.

Ethics declarations

Conflict of interest

Authors Refaat A Eid, Samah A Alharbi, Attalla Farag El-kott, Samy M Eleawa, Mohamed Samir Ahmed Zaki, Fahmy El-Sayed, Muhammad Alaa Eldin, Hussain Aldera, and Abd Al-Rahman Salem Alshudiefat declare that they havo no conflicts of interest.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Eid, R.A., Alharbi, S.A., El-kott, A.F. et al. Exendin-4 Ameliorates Cardiac Remodeling in Experimentally Induced Myocardial Infarction in Rats by Inhibiting PARP1/NF-κB Axis in A SIRT1-Dependent Mechanism. Cardiovasc Toxicol 20, 401–418 (2020). https://doi.org/10.1007/s12012-020-09567-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12012-020-09567-5

Keywords

Search

Navigation