Ameliorative effect of lixisenatide on diabetic cardiovascular damage and its enhancement via ticagrelor co-administration in rats: possible role of eNOS and NrF₂ /HO-1 signaling.

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In this study, we hypothesized that lixisenatide (LIX) and ticagrelor (TIC) could have a protective effect against type 2 diabetes mellitus (T2DM)-induced vascular damage. Furthermore, we explored the possible additional protective effect of co-administering LIX and TIC in the treatment regimen. Methods: 50 male rats were divided into five groups, each comprising 10 rats: C (control), D (T2DM rats), D + LIX (T2DM rats treated with LIX for 4 weeks), D + TIC (T2DM rats treated with TIC for 4 weeks), and D + LIX + TIC (T2DM rats treated with LIX + TIC for 4 weeks). Results: The D group showed an increase in body weight, blood glucose, hemostatic model assessment for insulin resistance (HOMA-IR), aorta reactive oxygen species (ROS), and nuclear factor kappa B (NF-κ B), along with a reduction in serum insulin, aorta superoxide dismutase (SOD), glutathione reduced (GSH), nuclear factor erythroid-2 (NrF₂), hemeoxygenase-1 (HO-1), and endothelial nitric oxide synthase (eNOS). Deterioration in the aorta histopathological condition, coupled with a noticeable impairment in vascular reactivity compared to the C group, was observed. A single administration of LIX showed a reduction in body weight, blood glucose, HOMA-IR, aorta ROS, and NF-κ B, accompanied by an increase in serum insulin, aorta SOD, GSH, NrF₂, HO-1, and eNOS. Amelioration in the aorta histopathological condition and improved vascular reactivity compared to the D group were reported. Similarly, a single administration of TIC showed a reduction in aorta ROS and NF-κ B, along with an increase in aorta SOD, GSH, NrF₂, HO-1, and eNOS. A slight amelioration was detected in the aorta histopathological condition, with improved vascular reactivity compared to the D group. The combined administration of LIX and TIC showed a reduction in aorta ROS and NF-κ B, along with an increase in aorta GSH, SOD, HO-1, and eNOS. This was combined with evident amelioration in the aorta histopathological condition and noticeable improvement in vascular reactivity compared to the single treatment with either LIX or TIC group. Conclusion: The present study introduces clear evidence that the administration of LIX and TIC can improve metabolic and vascular complications of T2DM through modulating eNOS and NrF₂ /HO-1 signaling. The combined administration of LIX and TIC produced more significant effects than a single treatment.