Repaglinide Provokes Dose‐Dependent Myocardial Toxicity via Disrupting HIF‐1α, TLR4/MyD88, and NF‐κB Pathway: A Biochemical, Radiological, and Histological Approach

Repaglinide (RPG) is a commonly prescribed oral antihyperglycemic agent for the control of postprandial hyperglycemia. However, the safety profile of RPG regarding cardiac tissues has not been explored yet. The present study examined the cardiotoxic effects of RPG in male Sprague Dawley rats at different doses using integrated molecular, biochemical, functional and histopathological approaches. Thirty-two rats were randomly allocated to four groups (n = 8), that is, control and RPG-treated (0.7, 1.4, and 4 mg/kg/day) groups for 4 weeks. RPG administration significantly upregulated hypoxia-angiogenic markers (HIF-1α, VEGF-A, VEGFR-2, and EPO) and downregulated ANGPT1, which is suggestive of disrupted vascular stabilization. A strong inflammatory response was noticed with marked activation of TLR4/MyD88/NF-κB signaling and increased COX-2, IL-6, IL-1β, and TNF-α expression. Oxidative stress was markedly increased at a dose-dependent manner, as shown by degradation in antioxidant enzyme (CAT, SOD, GSR, GPx, GST, and HO-1,) and high increments in MDA and ROS levels. Echocardiographic analysis showed a gradual low heart rate, ventricular dilation, thickening of the ventricular walls, and increasing of EDV and ESV, which is a sign of structural remodeling and impairment of the ventricle. Serum cardiac biomarkers (CK-MB, CPK, Troponin-I, Troponin-T, LDH, BNP, NT-proBNP, and CRP) were significantly elevated following the administration of RPG at varying concentrations. Apoptotic signaling was activated significantly as shown by the increased levels of Bax, Caspase-3, and Caspase-9 with reduced expression of Bcl-2 after RPG intoxication. Moreover, RPG exposure induced histopathological alterations including degenerative myocardial lesions, interstitial edema, inflammatory infiltration, and early fibrotic changes. Collectively, these results show that RPG causes profound cardiotoxicity in a dose-dependent manner, mediated by oxidative stress, inflammatory activation, hypoxia-angiogenic imbalance, apoptotic signaling, and structural remodeling. This study demonstrates the importance of thorough cardiovascular safety evaluation of antidiabetic therapies and calls for further translational evaluation to evaluate potential clinical implications.