Exendin-4 induces myocardial protection through MKK3 and Akt-1 in infarcted hearts

Abstract

-We have demonstrated that glucagon like peptide-1 (GLP-1) protects the heart against ischemic injury. However, the physiological mechanism by which GLP-1 receptor (GLP-1R) initiates cardioprotection remains to be determined. The objective of this study is to elucidate the functional roles of MAPK kinase 3 (MKK3) and Akt-1 in mediating exendin-4-elicited protection in the infarcted hearts. Adult mouse myocardial infarction (MI) was created by ligation of the left descending artery. Wild-type, MKK3Ϫ/Ϫ , Akt-1 Ϫ/Ϫ , and Akt-1 Ϫ/Ϫ ; MKK3 Ϫ/Ϫ mice were divided into one of several groups: 1) sham: animals underwent thoracotomy without ligation; 2) MI: animals underwent MI and received a daily dose of intraperitoneal injection of vehicle (saline); 3) MI ϩ exendin-4: infarcted mice received daily injections of exendin-4, a GLP-1R agonist (0.1 mg/kg, ip). Echocardiographic measurements indicate that exendin-4 treatment resulted in the preservation of ventricular function and increases in the survival rate, but these effects were diminished in MKK3 Ϫ/Ϫ , Akt-1 Ϫ/Ϫ , and Akt-1 Ϫ/Ϫ ;MKK3 Ϫ/Ϫ mice. Exendin-4 treatments suppressed cardiac hypotrophy and reduced scar size and cardiac interstitial fibrosis, respectively, but these beneficial effects were lost in genetic elimination of MKK3, Akt-1, or Akt-1 Ϫ/Ϫ ;MKK3 Ϫ/Ϫ mice. GLP-1R stimulation stimulated angiogenic responses, which were also mitigated by deletion of MKK3 and Akt-1. Exendin-4 treatment increased phosphorylation of MKK3, p38, and Akt-1 at Ser129 but decreased levels of active caspase-3 and cleaved poly (ADP-ribose) polymerase; these proteins were diminished in MKK3 Ϫ/Ϫ , Akt-1 Ϫ/Ϫ , and Akt-1 Ϫ/Ϫ ; MKK3 Ϫ/Ϫ mice. These results reveal that exendin-4 treatment improves cardiac function, attenuates cardiac remodeling, and promotes angiogenesis in the infarcted myocardium through MKK3 and Akt-1 pathway.glucagon-like peptide-1 receptor; MAPK kinase 3; Akt-1; myocardial infarction; function GLUCAGON-LIKE PEPTIDE-1 (GLP-1) is a naturally occurring incretin that is implicated in the control of appetite and satiety (23). GLP-1 has been studied extensively in type 2 diabetes as a novel insulinotropic peptide whose actions are dependent on the ambient glucose concentration. GLP-1 acts through the GLP-1 receptor (GLP-1R), a 463-amino acid member of the G protein-coupled receptor superfamily (23). GLP-1 is rapidly cleaved by dipeptidyl-peptidase-4 (DPP4), which results in the generation of largely inactive molecular GLP-1 9 -36 amide and GLP-1 9 -37 forms (14). The majority of GLP-1 leaving the intestinal venous circulation has already been cleaved by DPP4 expressed in capillary surrounding gut L cells, which provides an estimated half-life of 1-2 min for intact GLP-1 in vivo (12). The GLP-1 receptor is widely distributed in tissues, including brain, pancreas, intestine, lung, stomach, and kidney. Recently, multiple GLP-1 receptor agonists with longer duration of effect in vivo have been explored, among which is exendin-4, a 39-amino acid peptide that shares 53% sequence ho...

Sodium Butyrate Protects ­Against High Fat Diet-Induced Cardiac Dysfunction and Metabolic Disorders in Type II Diabetic Mice

“…Previous work has demonstrated that p38 phosphorylation was closely associated with insulin improvement and beneficial effects in diabetic hearts [Zhao et al, ; Bhashyam et al, ]. We have also demonstrated that genetic inhibition of MKK3/p38 and Akt‐1 abolished the protective effects of GLP‐1 receptor‐induced protective effects [Du et al, ]. In this observation, we found that a high fat diet induced the attenuation of phosphorylated MKK3 and p38, which were prevented by supplying sodium butyrate.…”

Exendin‐4 protects the hearts of rats from ischaemia/reperfusion injury by boosting antioxidant levels and inhibition of JNK/p66Shc/NADPH axis

“…Supporting our data, the cardioprotective effect of GLP‐1 and different GLP1 agonists has been shown in various animal models of oxidative stress‐induced cardiac damage including obesity, diabetic cardiomyopathy, and I/R, as well as in patients with diagnosed MI on admission 25,27‐31,46,47 . Also, Exendin‐4 improved cardiac function and inhibited ROS generation and apoptosis in diabetic rats by activating cAMP/PKA signalling pathways and concomitant upregulation of MnSOD and catalase (CAT) 48,49 .…”

GLP-1R as a Target for the Treatment of Diabetic Retinopathy: Friend or Foe?

“…Recent studies have revealed that GLP-1 enhances proliferation and differentiation of endothelial progenitor cells through upregulation of VEGF (37). In addition, there is emerging experimental evidence indicating the angiogenic effects of GLP-1RA using human umbilical vein endothelial cells (38,39), or in in vivo models of hind-limb ischemic injury (40,41) and myocardial infarction (42,43). Therefore, it might be hypothesized that the worsening of DR observed in the SUSTAIN study could be partially accounted for by the inclusion of patients with advanced nonproliferative DR or proliferative DR (stages in which hypoxia plays a crucial pathogenic role) in whom semaglutide could have triggered angiogenesis, thus favoring neovascularization.…”