Discrepancy between the Actions of Glucagon-like Peptide-1 Receptor Ligands in the Protection of the Heart against Ischemia Reperfusion Injury

Abstract

Tirzepatide is a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist and a promising therapy for type 2 diabetes mellitus (T2DM). GLP-1 is an incretin hormone with therapeutic potential beyond type 2 diabetes mellitus. However, GLP-1 is rapidly degraded by dipeptdyl peptidase-IV (DPP-IV) to GLP-1 (9-36). Exendin-4 (Ex-4) is a DPP-IV-resistant GLP-1 receptor agonist which, when truncated to Ex-4 (9-39), acts as a GLP-1 receptor antagonist. In the present study, hearts isolated from Wistar rats (n = 8 per group) were perfused with a modified Langendorff preparation. Left ventricular (LV) contractility and cardiovascular hemodynamics were evaluated by a data acquisition program and infarct size was evaluated by 2,3,5-Triphenyl-2H-tetrazolium chloride (TTC) staining and cardiac enzyme levels. Hearts were subjected to 30 min regional ischemia, produced by ligation of the left anterior descending (LAD) coronary artery followed by 30 min reperfusion. Hearts were treated during reperfusion with either the non-lipidated precursor of tirzepatide (NLT), GLP-1, GLP-1 (9-36), or Ex-4 in the presence or absence of Ex-4 (9-39). Infusion of GLP-1 (9-36) or Ex-4 protected the heart against I/R injury (p > 0.01) by normalizing cardiac hemodynamic and enzyme levels. Neither GLP-1, NLT, nor Ex-4 (9-39) showed any protection. Interestingly, Ex-4 (9-39) blocked Ex-4-mediated protection but not that of GLP-1 (9-36). These data suggest that Ex-4-mediated protection is GLP-1-receptor-dependent but GLP-1 (9-36)-mediated protection is not.

Renin–Angiotensin System Antagonism Protects the Diabetic Heart from Ischemia/Reperfusion Injury in Variable Hyperglycemia Duration Settings by a Glucose Transporter Type 4-Mediated Pathway

“…Anesthesia was performed with intraperitoneal injections of sodium pentobarbital (60 mg/kg) and the animals were anticoagulated by heparin (1000 U/kg). Heart mounting cannulation and perfusion were done as described previously [ 59 , 60 ]. Briefly, isolated heart was reversely perfused with a freshly prepared Krebs–Hensleit (KH) buffer, pH 7.35 to 7.45 at 37.0 ± 0.5 °C and was gassed with CO 2 (5%) and O 2 (95%).…”

Effects of Apocynin, a NADPH Oxidase Inhibitor, in the Protection of the Heart from Ischemia/Reperfusion Injury

“…Immediately after the isolation process, the heart was cannulated to a modified Langendorff system, as described previously [49,50]. To fix the heart to the modified Langendorff system, a cannula was inserted in the aorta and was stabilized by a small clip.…”

Peptides Are Cardioprotective Drugs of the Future: The Receptor and Signaling Mechanisms of the Cardioprotective Effect of Glucagon-like Peptide-1 Receptor Agonists

“…The GLP1R antagonist exendin (9-39) eliminated the cardioprotective effect of exendin-4 but did not affect the cardioprotective effect of GLP-1(9-36) [42]. It was concluded that the protective effect of exendin-4 is accompanied by the activation of the GLP1R, and the protective effect of GLP-1(9-36) does not depend on stimulation of this receptor [42]. CAO (30 min) and reperfusion were carried out in rats [43].…”

“…Isolated rat hearts were exposed to regional ischemia (30 min) and reperfusion (30 min) [42]. The hearts were perfused with a solution containing exendin-4 (100 nmol/L) or GLP-1(9-36) (100 nmol/L) 5 min before reperfusion and perfusion was continued for 10 min of reperfusion.…”