Cardiac sirtuin1 deficiency exacerbates ferroptosis in doxorubicin-induced cardiac injury through the Nrf2/Keap1 pathway.

Doxorubicin (DOX), a broad-spectrum chemotherapeutic agent for various cancers, has limited clinical application because of its serious cardiotoxicity, which is due to different mechanisms, including cardiac ferroptosis and oxidative stress. Some drugs, such as berberine or dioscin, show efficacy in impeding DOX-induced cardiotoxicity by activating Sirtuin 1 (Sirt1). However, there is no direct evidence to clarify the role of Sirt1 in DOX-induced cardiomyopathy and its underlying role in cardiac ferroptosis. In this study, C57BL/6 and cardiac-specific Sirt1-/- knockout mice were used as a DOX-induced cardiotoxicity model. We found that cardiac Sirt1 was downregulated, oxidative stress was increased and ferroptosis were obviously enhanced, as reflected by decreased Glutathione peroxidase 4 (GPX4) and increased Heme oxygenase 1 (Hmox-1), exposure to DOX treatment in mice and H9c2 cells compared with the control. And Sirt1 activation was resistant to cardiac injury induced by DOX, as observed the improvement of cardiac dysfunction, and the reduction of cardiac fibrosis. However, cardiac Sirt1 deficiency aggravated Dox-induced cardiac dysfunction and cardiac remodeling, further downregulated GPX4, upregulated Hmox-1 expression and increased ROS level. In addition, Sirt1-siRNA exacerbated DOX-induced cardiotoxicity in H9c2 cells, which is similar to the results obtained in vivo. Furthermore, DOX decrease Nrf2 translocation from the cytosol to the nucleus, and Sirt1 deficiency further restrain the process, as well as the downstream Keap1 pathways, in DOX-induced cardiotoxicity. This study provides direct evidence that Sirt1 plays a protective role in DOX-induced cardiotoxicity by mediating ferroptosis reduction via the Nrf2/Keap1 pathway.

Efficacy and safety of sacubitril valsartan in treating heart failure with midrange ejection fraction after acute myocardial infarction in diabetic patients.

ABSTRACT: Objective to evaluate the clinical efficacy and safety of sacubitril valsartan in the treatment of heart failure (HF) with midrange ejection fraction after acute myocardial infarction (AMI) in diabetic patients. From January 2015 to July 2020, HF patients with diabetes mellitus complicated with AMI were retrospectively analyzed. According to the medication, they were divided into 2 groups, that is, sacubitril valsartan group (84 cases) and valsartan group (86 cases). Valsartan group took valsartan capsule (80 mg/capsule, Beijing Novartis Pharmaceutical Co., Ltd) 80 mg, qd, on the basis of routine treatment. On the basis of routine treatment, the sacubitril valsartan group took sacubitril valsartan sodium tablets (50 mg/tablet, Beijing Novartis Pharmaceutical Co., Ltd), the initial dose was 25 mg, bid, and gradually increased to the target dose according to the patient's blood pressure. After 12 months of treatment, the independent sample t test showed that the left ventricular end diastolic dimension in the sacubitril valsartan group was lower than that in the valsartan group [(47.26 ±â€Š4.71) mm vs (50.05 ±â€Š5.62) mm, P < .001]. The left ventricular ejection fraction in the sacubitril valsartan group was higher than that in the valsartan group [(54.76 ±â€Š4.24)% vs (49.28 ±â€Š3.74)%, P < .001]. χ2 inspection showed that the readmission rate in the sacubitril valsartan group was lower than that in the valsartan group (7.14% vs 18.60%, P < .05). Sacubitril valsartan has good safety and tolerability in patients with diabetes mellitus complicated with AMI who have HF with midrange ejection fraction. Compared with valsartan, sacubitril valsartan can improve the left ventricular function better and reduce the readmission rate due to HF in these patients.