High Salt Exacerbates Myocardial Dysfunction In Vitro and In Vivo by Promoting SIRT1/Nrf2‐Mediated Ferroptosis

Myocardial dysfunction is a crucial determinant of the development of heart failure in salt-sensitive hypertension. Ferroptosis, a programmed iron-dependent cell death, has been increasingly recognised as an important contributor to the pathophysiology of various cardiovascular diseases. This study aims to investigate the role and underlying mechanism of ferroptosis in high-salt (HS)-induced myocardial damage. Our results reveal that HS stimulation inhibited cell proliferation and promoted apoptosis in cardiomyocyte HL-1 cells in a dose-dependent manner. Ferroptotic features were observed in HS-induced HL-1 cells, including ferric iron accumulation, decreased glutathione levels, increased oxidative stress levels, upregulation of ferroptosis marker proteins PTGS2, 4HNE and FTH1 and downregulation of GPX4, all of which were reversed by treatment with the ferroptosis suppressor Fer-1. Furthermore, the administration of Fer-1 ameliorated HS-induced ferroptosis and myocardial damage in salt-sensitive Dahl SS rats. Additionally, we found that a HS diet suppressed the SIRT1/Nrf2 signalling pathway activation in our in vivo experiments. Activation of SIRT1/Nrf2 signalling by SIRT1 overexpression significantly attenuated ferroptosis in HS-induced HL-1 cells. In conclusion, our findings demonstrate that HS levels induce myocardial injury by promoting ferroptosis via the deactivation of the SIRT1/Nrf2 signalling pathway, highlighting the potential for therapeutic targeting of ferroptosis for hypertension-related cardiovascular disorders.