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

Figures

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  Figure 1. GLP-1 protection of the heart against ischemia reperfusion injury (n = 8 per group). Post-ischemic recovery in myocardial hemodynamics (A) DPmax, and (B) LVEDP, (C) CF and (D) CVR. The data were computed at 30 min reperfusion and are expressed as means ± SEM. Ctr, control; DPmax, maximum developed pressure; LVEDP, left ventricular end diastolic pressure; CF, coronary flow; CVR, coronary vascular resistance. * p < 0.001 compared to respective control. † p < 0.001 compared to ischemic period.

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  Figure 2. Post-ischemic infarct size in different treatment groups. Post-infarct size is significantly reduced with the introduction of Ex-4, GLP-1(9-36), and GLP-1 (9-36) + Ex-4 (9-39). Ctr, control; GLP-1, glucagon-like peptide-1; GLP-1 (9-36), glucagon-like peptide-1 (9-36); Ex-4 (9-39), exendin-4 (9-39); Ex-4, exendin-4. * p < 0.01 compared to the control group.

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  Figure 3. Post-ischemic recovery of CVR in the presence of exendin-4 and NLT infused before ischemia or at reperfusion. (A) DPmax, and (B) LVEDP, (C) CF and (D) CVR. No significant improvement in CVR was appreciated in the displayed treatment groups. The data were collected after 25 min of ischemia and 30 min of reperfusion and are presented as means ± SE. CVR, coronary vascular resistance; Ex-4, exendin-4; NLT Pre, non-lipidated tirzepatide pre-ischemia; NLT Post, non-lipidated tirzepatide post-ischemia, * p < 0.05 compared to the control group. † p < 0.05 compared to the respective ischemic period.

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  Figure 4. Post-ischemic infarct size in different treatment groups. Post-ischemic infarct size was not reduced by the introduction of NLT pre- and post-ischemia. Ctr, control; Ex-4, exendin-4; NLT Pre, non-lipidated tirzepatide pre-ischemia; NLT Post, non-lipidated tirzepatide post-ischemia. * p < 0.01 compared to the control group.

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  Figure 5. Post-ischemic recovery of CVR in the presence of exendin-4 + exendin-4 (9-39) and GLP-1(9-36) + exendin-4 (9-39). (A) DPmax, and (B) LVEDP, (C) CF and (D) CVR. The data were collected after 25 min of ischemia and 30 min of repefusion and are presented as means ± SE. LVEDP, left ventricular end diastolic pressure; DPmax, maximum developed pressure; Ex-4, exendin-4; GLP-1 (9-36), glucagon-like peptide-1 (9-36); Ex-4 (9-39), exendin-4 (9-39). * p < 0.05 compared to the control group; † p < 0.05 compared to the respective ischemic period.

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  Figure 6. Post-ischemic reduction of (A) TNF-α, (B) IL-1β, and (C) IL-6 levels. Ctr, control; GLP-1, glucagon-like peptide-1; GLP-1 (9-36), glucagon-like peptide-1 (9-36); Ex-4 (9-39), exendin-4 (9-39); Ex-4, exendin-4; NLT Pre, non-lipidated tirzepatide pre-ischemia; NLT Post, non-lipidated tirzepatide post-ischemia. * p < 0.01 compared to the control group.

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  Figure 7. Post-ischemic recovery of (A) CAT and (B) SOD activity. Ctr, control; GLP-1 (9-36), glucagon-like peptide-1 (9-36); Ex-4 (9-39), exendin-4 (9-39); Ex-4, exendin-4; NLT Pre, non-lipidated tirzepatide pre-ischemia; NLT Post, non-lipidated tirzepatide post-ischemia. * p < 0.01 compared to the control group.

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  Figure 8. Schematic representation showing the experimental protocols used for the study (n = 8 per group). (A) Unprotected ischemia-reperfusion (control). (B) Infusion with GLP-1, GLP-1 (9-36), and Ex-4 (C) Infusion of non-lipidated precursor of tirzepatide. (D) Infusion with GLP-1, GLP-1 (9-36), and Ex-4 in presence of Ex-4 (9-39).

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  Figure 9. Schematic representation showing the interactions between I/R injury and GLP-1 related peptides. Ischemia/reperfusion-induced cardiac injury characterized by impaired cardiac hemodynamics and enhanced release of cardiac enzymes, LDH, and CK. GLP-1 (9-36) and Ex-4 treatment improved cardiac hemodynamic and attenuated release of cardiac enzymes. Ex-4 protection involved downstream signaling via the GLP-1 receptor; however, the protection elicited by GLP-1(9-36) appears to be GLP-1-receptor independent.