Copper is a vital mineral, and an optimal amount of copper is required to support normal physiologic processes in various systems, including the cardiovascular system. Over the past few decades, copper-induced cell death, named cuproptosis, has become increasingly recognized as an important process mediating the pathogenesis and progression of cardiovascular disease (CVD), including atherosclerosis, stroke, ischemia-reperfusion injury, and heart failure. Therefore, an in-depth understanding of the regulatory mechanisms of cuproptosis in CVD may be useful for improving CVD management. Here, we review the relationship between copper homeostasis and cuproptosis-related pathways in CVD, as well as therapeutic strategies addressing copper-induced cell death in CVD.
Skimmin, a natural coumarin derivate, has been showed to be protective against experimental diabetic nephropathy; however, its protective effect on diabetic cardiomyopathy (DCM) is not clarified. By using in vitro and in vivo models, we investigated skimmin's protective effect on impaired heart tissues in DCM. DCM was induced by streptozotocin (STZ, 60 mg/kg) using Sprague Dawley rats, and diabetic rats were treated with either skimmin (15 or 30 mg/kg) or the vehicle for 16 weeks, and normal rats were used as a control. Hematoxylin and eosin and Masson's trichrome staining were performed to evaluate the cardiac histopathology, and the oxidative stress and proinflammation cytokines in heart tissues were measured. The protein levels of key mediators in fibrosis, pyroptosis, and autophagy in heart tissues were investigated using western blotting. In vitro, primary neonatal cardiomyocytes were treated with skimmin (2 and 10 μM) under stimulation by high glucose (30 mM) and low glucose (5 mM) respectively, and the molecular mechanisms on pyroptosis and autophagy were studied. Compared to the vehicle‐treated DCM group, skimmin treatment significantly improved the ejection fraction and fractional shortening of the left ventricle and reduced the oxidative stress by increasing the glutathione level and activity of superoxide dismutase and catalase. Skimmin also reduced cardiac fibrosis, and decreased proinflammation cytokines in cardiac tissues. Mechanism studies showed skimmin may enhance the autophagy and ameliorate NLRP3 inflammasome activation to play a protective role in DCM. This study, for the first time, indicates that skimmin might be a promising lead compound for DCM.
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