Pharmacological inhibition of apoptosis, necroptosis, and ferroptosis confers effective cardioprotection in post-myocardial infarction in rats

Abstract

Cardiovascular conditions account for millions of deaths globally. Myocardial infarction (MI) remains the foremost cause of cardiovascular death. Post-MI pathology can activate a diverse type of programmed cell death (PCD), which aggravates cardiac dysfunction and causes post-ischemic heart failure. Although various PCD inhibitors have shown potential efficacy against several cardiac complications, their roles in preventing or reducing myocardial loss and dysfunction in post-MI pathology have never been clarified. A rat model of MI was used in this study and post-MI rats were randomly assigned into 5 subgroups (n = 7/group): (1) vehicle (3%V/V DMSO), (2) enalapril (10 mg/kg), (3) zVAD-FMK (1 mg/kg), (4) Necrostatin-1 (1.65 mg/kg), or (5) Ferrostatin-1 (2 mg/kg). All treatments were given for 32 days via intraperitoneal injection. A control group of sham-operated rats underwent thoracotomy without left anterior descending (LAD) artery occlusion (n = 7). After 32 days of treatment, echocardiography and ventricular pressure-volume (P-V) loop studies, mitochondrial function, histopathological studies, and molecular analysis were carried out. Treatment with zVAD-FMK, Necrostatin-1, and Ferrostatin-1 mitigated pathological cardiac remodeling, reduced apoptosis and necroptosis-mediated myocardial injury, alleviated mitochondrial dysfunction, and improved cardiac function in post-MI rats. These findings indicated that inhibition of apoptosis and necroptosis could be novel strategies for treatment in post-MI conditions.