ABSTRACT
Herein, we define the role of ferroptosis in the pathogenesis of diabetic cardiomyopathy (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. This suggests a feasible therapeutic approach with sulforaphane to clinically prevent ferroptosis and DCM.
ABSTRACT
BACKGROUND: Patches, powders and hydrogels fabricated from extracellular matrix and its components can be used as scaffolds, along with a variety of stem cells and their derivatives, to construct biomimetic engineered cardiac tissue. OBJECTIVE: To review research progress in construction of biomimetic engineered cardiac tissue based on extracellular matrix. METHODS: We searched the articles in Web of Science Core Collection and PubMed databases with the key words of “the extracellular matrix; engineered cardiac tissue; cardiomyocyte; biomimetic; stem cell” in English. Eventually 64 articles were included for review. RESULTS AND CONCLUSION: Compared with the traditional synthetic materials, the extracellular matrix has good biocompatibility and cell affinity, which can provide seed cells with the closest living environment, and is conducive to the growth, differentiation and maturation of seed cells. A great number of research evidences suggest that the biomimetic engineered cardiac tissue based on extracellular matrix and stem cells has the characteristics of excitability, contractility and conductivity similar to the natural myocardial tissue. It also can repair the damaged myocardium, reshape the microvascular system and effectively improve cardiac function, showing the potential to treat cardiovascular diseases such as myocardial infarction. However, there are still some problems in the construction of biomimetic engineered cardiac tissue based on extracellular matrix, such as the structural damage during decellularization, the relatively slow development of seed cell morphology and function.