Role of the integrin-linked kinase/TGF-β/SMAD pathway in sitagliptin-mediated cardioprotective effects in a rat model of diabetic cardiomyopathy

Abstract Objectives Diabetic cardiomyopathy is a known complication of diabetes mellitus. Herein, we aimed to determine whether glycemic control mediated by sitagliptin, a dipeptidyl peptidase-4 inhibitor, can ameliorate diabetic myocardial abnormalities by modulating TGF-β signaling via the SMAD an...

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Published in:Journal of pharmacy and pharmacology 2024-01, Vol.76 (1), p.64-73
Main Authors: Bin Dayel, Anfal F, Alonazi, Asma S, Alrasheed, Nawal M, Alamin, Maha A, Sarawi, Wedad S, Alharbi, Abeer O, Alabbad, Nahla’a A, Albuaijan, Danah A, Alassiri, Dareen N, Aljarbua, Alanoud F, Almusaytir, Fatimah K, Alrasheed, Nouf M
Format: Article
Language:English
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Summary:Abstract Objectives Diabetic cardiomyopathy is a known complication of diabetes mellitus. Herein, we aimed to determine whether glycemic control mediated by sitagliptin, a dipeptidyl peptidase-4 inhibitor, can ameliorate diabetic myocardial abnormalities by modulating TGF-β signaling via the SMAD and integrin-linked kinase (ILK) pathways. Methods Four groups of male Wistar albino rats were used, with six rats in each group. Two nondiabetic and two diabetic (produced by a single intraperitoneal dose of streptozotocin (55 mg/kg)) groups were administered either normal saline or sitagliptin (100 mg/kg) orally for 6 weeks. Subsequently, HW/BW ratios and cardiac enzymes were assessed, along with a histological examination of cardiac tissues. Levels of TGF-β, collagen I, p-SMAD2/3, TNF-α, MMP-9, and ILK were detected. Results Compared with the diabetic control group, sitagliptin-treated diabetic rats exhibited considerably reduced HW/BW ratios and troponin I and creatine kinase-MB levels, with improvements in histopathological changes in cardiac tissues. TGF-β, collagen I, p-SMAD2/3, TNF-α, and MMP-9 levels were significantly decreased in the sitagliptin-treated diabetic group, whereas ILK was elevated following sitagliptin treatment. Conclusion Sitagliptin could afford cardioprotective effects for the first time by altering ILK-associated TGF-β/SMAD signaling pathways. Thus, sitagliptin may be a promising therapeutic target for the prevention of diabetic cardiomyopathy.
ISSN:0022-3573
2042-7158
DOI:10.1093/jpp/rgad111