Combination therapy with deferasirox and cyclosporine A synergistically reduced infarct size (37±3% vs 64±2% for control) in a mouse model of myocardial ischemia reperfusion injury.
Does combination therapy with deferasirox and cyclosporine A reduce infarct size and ameliorate adverse cardiac remodeling in a mouse model of myocardial ischemia reperfusion injury?
Combination therapy with deferasirox and cyclosporine A synergistically reduces infarct size and ameliorates adverse cardiac remodeling in a mouse model of myocardial ischemia reperfusion injury.
Absolute Event Rate: 37% vs 64%
BACKGROUND: Ferroptosis, an iron-dependent form of regulated cell death, is a major cell death mode in myocardial ischemia reperfusion (I/R) injury, along with mitochondrial permeability transition-driven necrosis, which is inhibited by cyclosporine A (CsA). However, therapeutics targeting ferroptosis during myocardial I/R injury have not yet been developed. Hence, we aimed to investigate the therapeutic efficacy of deferasirox, an iron chelator, against hypoxia/reoxygenation-induced ferroptosis in cultured cardiomyocytes and myocardial I/R injury. METHODS AND RESULTS: The effects of deferasirox on hypoxia/reoxygenation-induced iron overload in the endoplasmic reticulum, lipid peroxidation, and ferroptosis were examined in cultured cardiomyocytes. In a mouse model of I/R injury, the infarct size and adverse cardiac remodeling were examined after treatment with deferasirox, CsA, or both in combination. Deferasirox suppressed hypoxia- or hypoxia/reoxygenation-induced iron overload in the endoplasmic reticulum, lipid peroxidation, and ferroptosis in cultured cardiomyocytes. Deferasirox treatment reduced iron levels in the endoplasmic reticulum and prevented increases in lipid peroxidation and ferroptosis in the I/R-injured myocardium 24 hours after I/R. Deferasirox and CsA independently reduced the infarct size after I/R injury to a similar degree, and combination therapy with deferasirox and CsA synergistically reduced the infarct size (infarct area/area at risk; control treatment: 64±2%; deferasirox treatment: 48±3%; CsA treatment: 48±4%; deferasirox+CsA treatment: 37±3%), thereby ameliorating adverse cardiac remodeling on day 14 after I/R. CONCLUSIONS: Combination therapy with deferasirox and CsA may be a clinically feasible and effective therapeutic approach for limiting I/R injury and ameliorating adverse cardiac remodeling after myocardial infarction.
Ishimaru et al. (Sat,) conducted a other in Myocardial ischemia reperfusion injury. Deferasirox and Cyclosporine A vs. Control treatment was evaluated on Infarct size (infarct area/area at risk). Combination therapy with deferasirox and cyclosporine A synergistically reduced infarct size (37±3% vs 64±2% for control) in a mouse model of myocardial ischemia reperfusion injury.
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