Dimethyl itaconate preserves cardiac function and reduces remodeling via anti-fibrotic actions in rats

Background Cardiac hypertrophy is a pathological condition associated with the enlargement of the heart muscle and serves as a risk factor for heart failure. Itaconic acid is a metabolite produced by immune cells, while dimethyl itaconate (DMI) is a derivative of itaconic acid. DMI is cell-permeable and possesses antioxidant and cytoprotective properties. Here, we studied the beneficial effects of DMI in experimental models of cardiac hypertrophy. Methods and results Isoproterenol (ISO) is a synthetic catecholamine that mimics chronic adrenergic stimulation, leading to myocardial stress, oxidative damage, and fibrosis. An ISO-induced cardiac hypertrophy model was established in vitro in H9c2 cardiomyoblast cells and in rats. Based on in vitro results in H9c2 cells, DMI decreased ISO-induced hypertrophy and reactive oxygen species, and abated cellular fibrogenesis by reducing collagen-1, α-smooth muscle actin (α-SMA), and transforming growth factor (TGF)-β expression. Echocardiography in rats revealed that DMI substantially preserved ISO-induced alterations in cardiac function parameters. Serum creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) levels were markedly decreased in the DMI-administered groups. Wheat germ agglutinin (WGA) staining also revealed that the DMI intervention reduced the cardiomyocyte size in the heart. The histopathological examination shows that DMI mitigates ISO-induced cardiac damage and also reduces collagen deposition and fibrosis in the heart. DMI treatment also enhanced myocardial antioxidant levels by restoring reduced glutathione (GSH), superoxide dismutase (SOD), and catalase levels. Conclusions Our study highlights the potential of DMI as a therapeutic agent in mitigating cardiac hypertrophy and fibrosis and offers insight into new treatment strategies for heart failure.