Methimazole induces dose-dependent cardiotoxicity via disrupting Hippo/YAP and calcium handling pathway: An echocardiographic, molecular, and histological investigation

Methimazole (MZL) is a widely prescribed antithyroid medication that has additionally been associated with unintended toxic effects involving organs outside its primary therapeutic site. The current work was conducted to investigate the progressive cardiac pathological alterations elicited by escalating dose levels of MZL. A total of 36 healthy (adult male albino rats) of comparable age and body weight were selected for the study after veterinary examination confirmed their suitability for experimental use. Selected animals were randomly distributed among the four experimental groups with each group having nine rats. Group I was designated as control group. Group II, III and IV were gavaged with MZL at a dose level of 60, 100 and 250 mg/kg/day body weight, respectively, continuously for 28 days. MZL treatment significantly and dose-dependently altered the expressions of MST1, LATS1, YAP1 and TEAD1. The genes for calcium-handling proteins were highly affected with a reduction in SERCA2a and RyR2 and an increase in PLN and NCX1 throughout the dose-escalation regimen of MZL. MZL intoxication significantly augmented ROS and MDA levels whereas suppressed SOD, CAT, GPx, GST, GSR, HO-1 and GSH. Echocardiographic evaluation showed cardiac remodeling, ventricular dilation, myocardial hypertrophy, and poor cardiac performance. There were significantly high level of cardiac biomarkers such as CK-MB, troponin-I, CPK, LDH, BNP, troponin-T, and NT-proBNP, signifying myocardial injury and ventricular dysfunction. Besides, MZL significantly worsened cardiac inflammation by elevating the expression of TNF-α, NF-κB, IL-6, IL-1β, and COX-2 and cardiac apoptosis by increasing caspase-3, Bax, & caspase-9, but diminishing Bcl-2. Histopathological examination showed myocardial degeneration, necrosis, edema, and inflammatory infiltration and structural disorganization in direct proportion to the administered dose. These findings showed severe myocardial toxicity following MZL intoxication throughout the investigated dose range thereby demonstrating its cardiotoxic manifestations.