Disruption of the caspase-1/IL-1β axis alleviates myocardial Ischemia/Reperfusion injury via improvement of mitochondrial homeostasis and reduction of Pyroptosis

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.
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.
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.
Overall, activating the Caspase-1/IL-1β axis by myocardial I/R injury causes mitochondrial homeostasis imbalance, pyroptosis, and the consequent cardiomyocyte injury.