Why the study?
Caspase-1 plays key roles in driving pyroptosis, but the molecular mechanism affecting cardiomyocyte pyroptosis in myocardial ischemia/reperfusion injury was not elucidated.
Knockdown of Caspase-1 protects against myocardial ischemia/reperfusion injury by reducing pyroptosis and improving mitochondrial homeostasis.
Supports Caspase-1 as a target in ischemia/reperfusion injury; hypothesis-generating for human translation.
BACKGROUND: Pyroptosis is a novel kind of programmed cell death and Caspase-1 plays key roles in driving pyroptosis. The current study aims to elucidate the molecular mechanism affecting cardiomyocyte pyroptosis in myocardial ischemia/reperfusion (I/R) injury, both in vivo and in vitro. METHODS: A murine model of myocardial I/R injury was established and then treated with lentivirus-mediated shRNA targeting Caspase-1 to evaluate the effect of Caspase-1 on myocardial I/R injury. Further, Caspase-1 was silenced in the cardiomyocytes following hypoxia-reoxygenation (H/R) to detect the function of Caspase-1 in mitochondrial homeostasis and cardiomyocyte pyroptosis. RESULTS: Knockdown of Caspase-1 inhibited the secretion of interleukin-1 beta (IL-1β), improved cardiac dysfunction and decreased pyroptosis in vivo. The cardio-protective effect was verified in the H/R-induced cardiomyocyte model. Recombinant IL-1β protein reversed the inhibitory effect of Caspase-1 knockdown on pyroptosis. CONCLUSION: Overall, activating the Caspase-1/IL-1β axis by myocardial I/R injury causes mitochondrial homeostasis imbalance, pyroptosis, and the consequent cardiomyocyte injury.
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Hu et al. (2025) studied this question.
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