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.

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. Graphical Abstract 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.