Diabetic cardiomyopathy and metal-mediated inflammation and cell deaths

Cardiac inflammation and myocyte death are essential for initiating the pathogenesis and progression of various etiological cardiomyopathies, including diabetic cardiomyopathy (DCM), reported in 1972. Cardiac cell death was detected in the hearts of patients with diabetes and animal models, and its role in the pathogenesis of DCM has been extensively investigated. Over the past several decades several new kinds of cell death, including apoptosis, necroptosis, pyroptosis, autophagy, ferroptosis, and cuproptosis were identified and mediated by different mechanisms. Although their roles in the pathogenesis of DCM have gained remarkable attention, I have been specifically worked on the metal-mediated cell deaths. In this presentation, therefore, I will report the role of ferroptosis in the pathogenesis of DCM by examining the expression of key regulators of ferroptosis in mice with DCM and a new ex vivo DCM model. Advanced glycation end-products (AGEs), an important pathogenic factor of DCM, were found to induce ferroptosis in engineered cardiac tissues (ECTs), as reflected through increased levels of Ptgs2 and lipid peroxides and decreased ferritin and SLC7A11 levels. Typical morphological changes of ferroptosis in cardiomyocytes were observed using transmission electron microscopy. Inhibition of ferroptosis with ferrostatin-1 and deferoxamine prevented AGE-induced ECT remodeling and dysfunction. Ferroptosis was also evidenced in the heart of type 2 diabetic mice with DCM. Inhibition of ferroptosis by liproxstatin-1 prevented the development of diastolic dysfunction at 3 months after the onset of diabetes. Nuclear factor erythroid 2-related factor 2 (NRF2) activated by sulforaphane inhibited cardiac cell ferroptosis in both AGE-treated ECTs and hearts of DCM mice by upregulating ferritin and SLC7A11 levels. The protective effect of sulforaphane on ferroptosis was AMP-activated protein kinase (AMPK)-dependent. These findings suggest that ferroptosis plays an essential role in the pathogenesis of DCM; sulforaphane prevents ferroptosis and associated pathogenesis via AMPK-mediated NRF2 activation. Then I will also report the impact of other metals such as copper, zinc and cadmium on the cell death and DCM. This presentation thus aims to stimulate further work in the field to advance the body of knowledge and continue to drive efforts to develop more advanced therapeutic approaches to prevent cell death, particularly metal-dependent cell death, and, ultimately, to reduce or prevent the development of DCM.

Dr. Cai, MD, PhD., is a tenured Professor of Departments of Pediatrics, Radiation Oncology and Pharmacology and Toxicology, and Director of Pediatric Research Institute, the University of Louisville School of Medicine. He is well-known expert world-wide in several fields: 1) diabetic cardiovascular diseases, focusing on the role of oxidative stress in the development of diabetic cardiomyopathy; 2) roles of trace elements (zinc, iron, copper, and cadmium and related metallothionein) in diabetic complications; 3) impact of environmental contamination of heavy metals such as cadmium on the victim and their offspring. He is author and co-author of more than 380 peer-reviewed publications, and served many journal editorial works as chief-editor and associated editor. Dr. Cai has ranked as top 10919 and 5538 of Best Medicine Scientists in world-wide and United States, respectively, with D- index 90 (total 24,332 citations).