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. 2024 Apr 19;17(4):525.
doi: 10.3390/ph17040525.

Effect of GLP-1 Receptor Agonist on Ischemia Reperfusion Injury in Rats with Metabolic Syndrome

Marko Ravic  1   2 , Ivan Srejovic  2   3   4 , Jovana Novakovic  1   2 , Marijana Andjic  1   2 , Jasmina Sretenovic  2   3 , Maja Muric  2   3 , Marina Nikolic  2   3 , Sergey Bolevich  5 , Kirill Alekseevich Kasabov  4 , Vladimir Petrovich Fisenko  4 , Aleksandra Stojanovic  1   2 , Vladimir Jakovljevic  2   3   5
Affiliations

Effect of GLP-1 Receptor Agonist on Ischemia Reperfusion Injury in Rats with Metabolic Syndrome

Marko Ravic et al. Pharmaceuticals (Basel). .

Abstract

Metabolic syndrome (MetS) represents an important factor that increases the risk of myocardial infarction, and more severe complications. Glucagon Like Peptide-1 Receptor Agonists (GLP-1RAs) exhibit cardioprotective potential, but their efficacy in MetS-related myocardial dysfunction has not been fully explored. Therefore, we aimed to assess the effects of exenatide and dulaglutide on heart function and redox balance in MetS-induced rats. Twenty-four Wistar albino rats with induced MetS were divided into three groups: MetS, exenatide-treated (5 µg/kg), dulaglutide-treated (0.6 mg/kg). After 6 weeks of treatment, in vivo heart function was assessed via echocardiography, while ex vivo function was evaluated using a Langendorff apparatus to simulate ischemia-reperfusion injury. Heart tissue samples were analyzed histologically, and oxidative stress biomarkers were measured spectrophotometrically from the coronary venous effluent. Both exenatide and dulaglutide significantly improved the ejection fraction by 3% and 7%, respectively, compared to the MetS group. Histological analyses corroborated these findings, revealing a reduction in the cross-sectional area of cardiomyocytes by 11% in the exenatide and 18% in the dulaglutide group, indicating reduced myocardial damage in GLP-1RA-treated rats. Our findings suggest strong cardioprotective potential of GLP-1RAs in MetS, with dulaglutide showing a slight advantage. Thus, both exenatide and dulaglutide are potentially promising targets for cardioprotection and reducing mortality in MetS patients.

Keywords: GLP-1 agonists; cardioprotection; metabolic syndrome; oxidative stress.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
(A) Effects of GLP-1RA on weight, (B) effect of GLP-RA on glycemia levels, (C) effect of GLP-1RA on glucose level during OGTT, (D) effect of GLP-1RA on insulin level during OGTT, (E) effect of GLP-1RA on systolic blood pressure. Values are presented as mean ± SD. Statistical significance at the level * p < 0.05, ** p < 0.01. MetS: metabolic syndrome group. Exenatide: group of rats treated with exenatide. Dulaglutide; group of rats treated with dulaglutide. BDA: before drug administration. 3rd week of DA: third week of drug administration. Before: before OGTT (glucose administration) a, #—MetS vs. Exenatide; b, &—MetS vs. Dulaglutide.
Figure 2
Figure 2
Effect of GLP-1RAs on cardiodynamic parameters: (A) dp/dt max—the maximum rate of LV pressure development, (B) dp/dt min—minimum rate of LV pressure development, (C) SLVP—systolic LV pressure, (D) DLVP—diastolic LV pressure, (E) HR—heart rate, and (F) CF—coronary flow. Values are presented as mean ± SD. Statistical significance at the level * p < 0.05, ** p < 0.01, *** p < 0.001. MetS: metabolic syndrome group; exenatide: group of rats treated with exenatide; dulaglutide; group of rats treated with dulaglutide. a—MetS vs. Exenatide; b—MetS vs. Dulaglutide. S—stabilization, I—ischemia, R—reperfusion.
Figure 3
Figure 3
Effect of GLP-1RAs on cardiodynamic parameters: (A) dp/dt max—the maximum rate of LV pressure development, (B) dp/dt min—minimum rate of LV pressure development, (C) SLVP—systolic LV pressure, (D) DLVP—diastolic LV pressure, (E) HR—heart rate, and (F) CF—coronary flow. Values are presented as mean ± SD, statistical significance at the level * p < 0.05, ** p < 0.01. MetS: metabolic syndrome group; exenatide: group of rats treated with exenatide; dulaglutide: group of rats treated with dulaglutide; S—stabilization period; 60′—60 (last) minute of reperfusion.
Figure 4
Figure 4
Effect of GLP-1RAs on pro-oxidants in coronary venous effluent: (A) TBARS—index of lipid peroxidation, (B) NO2−—nitrite, (C) O2−—superoxide anion radical and, (D) H2O2—hydrogen peroxide. Values are presented as mean ± SD. Statistical significance at the level * p < 0.05, ** p < 0.01, *** p < 0.001. MetS: metabolic syndrome group; exenatide: group of rats treated with exenatide; dulaglutide: group of rats treated with dulaglutide;. a—MetS vs. Exenatide; b—MetS vs. Dulaglutide; c—Exenatide vs. Dulaglutide. S—stabilization, I—ischemia, R—reperfusion.
Figure 5
Figure 5
Effect of GLP-1RAs on pro-oxidants in coronary venous effluent: (A) TBARS—index of lipid peroxidation, (B) NO2−—nitrite, (C) O2−—superoxide anion radical and, (D) H2O2—hydrogen peroxide. Values are presented as mean ± SD, statistical significance at the level ** p < 0.01, *** p < 0.001. MetS: metabolic syndrome group; exenatide: group of rats treated with exenatide; dulaglutide: group of rats treated with dulaglutide; S—stabilization period; 60′—60 (last) minute of reperfusion.
Figure 6
Figure 6
Representative micrograph of H&E staining of the cardiac muscle. Left row (objective magnification 20×, bar = 50 μm). Right row (objective magnification 40×, bar = 25 μm). METS: metabolic syndrome group; EXE: group of rats treated with exenatide; DULA: group of rats treated with dulaglutide. Graph represents values of the cross-section area of the cardiomyocyte of all groups. All values are the mean value ± SD. Statistical significance at the level * p < 0.05, ** p < 0.01 vs. the adequate group, connected by a horizontal line.
Figure 7
Figure 7
Representative micrographs of Picrosirius red-stained rat cardiac muscle sections (objective magnification 40×, bar = 20 μm; collagen fibers). METS: metabolic syndrome group; EXE: group of rats treated with exenatide; DULA: group of rats treated with dulaglutide. Graph represent quantification of collagen content (%) for all groups. All values are the mean value ± SD, statistical significance at the level * p < 0.05, ** p < 0.01 vs. the adequate group, connected by a horizontal line.
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