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Exendin-4 Attenuates Remodeling in the Remote Myocardium of Rats After an Acute Myocardial Infarction by Activating β-Arrestin-2, Protein Phosphatase 2A, and Glycogen Synthase Kinase-3 and Inhibiting β-Catenin

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Abstract

Purpose

This study tested if the protective anti-remodeling effect of GLP-1 agonist Exendin-4 after an acute myocardial infarction (MI) in rats involves inhibition of the Wnt1/β-catenin signaling pathway.

Methods

Rats were divided into sham, sham + Exendin-4 (10 μg/day, i.p), MI, and MI + Exendin-4. MI was introduced to rats by permanent left anterior descending coronary artery (LAD) ligation.

Results

On day 7 post-infraction, MI rats showed LV dysfunction with higher serum levels of cardiac markers. Their remote myocardia showed increased mRNA and protein levels of collagen I/III with higher levels of reactive oxygen species (ROS) and inflammatory cytokines, as well as protein levels of Wnt1, phospho-Akt, transforming growth factor (TGF-β1), Smad, phospho-Smad3, α-SMA, caspase-3, and Bax. They also showed higher protein levels of phospho-glycogen synthase kinase-3β (p-GSK3β), as well as total, phosphorylated, and nuclear β-catenin with a concomitant decrease in the levels of cyclic adenosine monophosphate (cAMP), mRNA of manganese superoxide dismutase (MnSOD), and protein levels of Bcl-2, β-arrestin-2, and protein phosphatase-2 (PP2A). Administration of Exendin-4 to MI rats reduced the infarct size and reversed the aforementioned signaling molecules without altering protein levels of TGF-1β and Wnt1 or Akt activation. Interestingly, Exendin-4 increased mRNA levels of MnSOD, protein levels of β-arrestin-2 and PP2A, and β-catenin phosphorylation but reduced the phosphorylation of GSK3β and Smad3, and total β-catenin levels in the LV of control rats.

Conclusion

Exendin-4 inhibits the remodeling in the remote myocardium of rats following acute MI by attenuating β-catenin activation and activating β-arrestin-2, PP2A, and GSK3β.

A graphical abstract that illustrates the mechanisms by which Exendin-4 inhibits cardiac remodeling in remote myocardium of left ventricle MI-induced rats. Mechanisms are assumed to occur in the cardiomyocytes and/or other resident cells such as fibroblast. Β-catenin activation and nuclear translocation are associated with increased synthesis of inflammatory cytokines and transforming growth factor β-1 (TGF-β1). GSK3β is inhibited by phosphorylation at Ser9. Under normal conditions, β-catenin is degraded in the cytoplasm by the active GSK3β-dependent degradation complex (un-phosphorylated) which usually phosphorylates β-catenin at Ser33/37/Thr41. After MI, TGF-β1, and Wnt 1 levels are significantly increased, the overproduction of Wnt1 induces β-catenin stabilization and nuclear translocation through increasing the phosphorylation of disheveled (DVL) protein which in turn phosphorylates and inhibits GSK3β. TGF-β1 stimulates the phosphorylation of Smad-3 and subsequent nuclear translocation to activate the transcription of collage 1/III and α-smooth muscle actin (α-SMA). Besides, TGF-β1 stabilizes cytoplasmic β-catenin levels indirectly by phosphorylation of Akt at Thr308-induced inhibition of GSK3β by increasing phosphorylation of Ser9. Exendin-4, and possibly through G protein-coupled receptors (GPCRs), increases levels of cAMP and upregulates β-arrestin-2 levels. Both can result in a positive inotropic effect. Besides, β-arrestin-2 can stimulate PP2A to dephosphorylation Smad3 (inhibition) and GSK3β (activation), thus reduces fibrosis and prevents the activation of β-catenin and collagen deposition.

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Funding

All authors extend their appreciation to the deanship of Scientific Research at King Khalid University, Abha, KSA, for funding this work through the research group program under grant number (R.G.P.1/46/40). Also, this research was funded by the Deanship of Scientific Research at Princess Nourah bint Abdulrahman University through the Fast-track Research Funding Program.

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Authors and Affiliations

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

    Refaat A. Eid, Mubarak Al-Shraim & Fahmy El-Sayed

  2. Department of Basic Medical Sciences, Faculty of Medicine, King Fahad Medical City, Riyadh, Saudi Arabia

    Mohammad Adnan Khalil

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

    Mahmoud A. Alkhateeb

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

    Samy M. Eleawa

  5. Department of Anatomy, College of Medicine, King Khalid University, Abha, Saudi Arabia

    Mohamed Samir Ahmed Zaki

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

    Mohamed Samir Ahmed Zaki

  7. Department of Biology, College of Science, King Khalid University, Abha, Saudi Arabia

    Attalla Farag El-kott

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

    Attalla Farag El-kott

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

    Muhammad Alaa Eldeen

  10. Department of Biology, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia

    Mashael Mohammed Bin-Meferij

  11. Clinical laboratories Department, Asser Central Hospital, Abha, Saudi Arabia

    Khalid M. E. Awaji

  12. Department of Clinical Cardiology, College of Medicine, King Khalid University, Abha, Saudi Arabia

    Abdullah S. Shatoor

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  1. Refaat A. Eid
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Contributions

Attalla El-kott obtained the fund. Refaat Eid, Attalla El-kott, Mahmoud Alkhateeb, Samy M Eleawa, and Abdullah Shatoor designed the experimental procedure and drafted the proposal. Mahmoud Alkhateeb established the animal model and collected samples and blood. Refaat Eid, Attalla Farag El-kott, Mohamed Samir Ahmed Zaki, Khalid Awaji, Mubarak Al-Shraim, Mashael Mohammed Bin-Meferij, Fahmy El-Sayed, and Muhammad Alaa Eldeen performed the biochemical analysis and histopathology and electron microscopy studies. Refaat Eid, Attalla El-kott, Mahmoud Alkhateeb, Samy M Eleawa, Abdullah Shatoor, and Mohammad Adnan Khalil drafted and revised several versions of the manuscript.

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Correspondence to Refaat A. Eid.

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Eid, R.A., Khalil, M.A., Alkhateeb, M.A. et al. Exendin-4 Attenuates Remodeling in the Remote Myocardium of Rats After an Acute Myocardial Infarction by Activating β-Arrestin-2, Protein Phosphatase 2A, and Glycogen Synthase Kinase-3 and Inhibiting β-Catenin. Cardiovasc Drugs Ther 35, 1095–1110 (2021). https://doi.org/10.1007/s10557-020-07006-9

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