Exploring the Role and Mechanism of DSF in HFpEF Based on IL-1β/IL-1βR/TAK1/RIPK1 Axis-Mediated PANoptosis.

Abstract

Heart failure with preserved ejection fraction (HFpEF) has a high prevalence and a low quality of life, and there are limited medications for the treatment of this disease. In recent years, disulfiram (DSF), an FDA-approved drug for the treatment of chronic alcohol addiction, has been found to have anti-inflammatory properties. The present study was designed to investigate the cardioprotective effects of DSF on patients with HFpEF and its mechanism using a model of HFpEF induced in mice fed a high-fat diet (HFD, 60% of calories from fat) and Nω-nitro-L-arginine methyl ester (L-NAME, 0.5 g/L in drinking water). The results showed that DSF effectively reversed the HFD + L-NAME-induced increases in left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), interventricular septal thickness, left ventricular mass, the ratio of peak early mitral diastolic velocity to peak late mitral diastolic velocity, the ratio of early mitral diastolic velocity to early diastolic velocity, as well as the reductions in the absolute value of global longitudinal strain (GLS), without affecting the left ventricular ejection fraction (LVEF). In addition, DSF notably attenuated the HFD + L-NAME-induced increase in blood pressure, exercise intolerance, cardiac hypertrophy, pulmonary edema, and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. Mechanistically, we found that DSF inhibited myocardial PANoptosis-like cell death, mainly by inhibiting the release of myocardial interleukin 1β (IL-1β), which inhibited transforming growth factor-β-activated kinase 1(TAK1)-mediated PANoptosis. Given the cardioprotective effects of DSF, its clinical use would be a novel strategy for the protection and treatment of cardiac injury in patients with HFpEF.