Sacubitril/valsartan attenuates myocardial ischemia/reperfusion injury via inhibition of the GSK3β/NF-ΚB pathway in cardiomyocytes

In ischemia/reperfusion (I/R) injury, both inflammation and apoptosis play a vital role, and the inhibition of excessive inflammation and apoptosis show substantial clinical potential in the treatment of I/R disease. The role of sacubitril/valsartan (SAC/VAL)-a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI)-in inflam-mation regulation and apoptosis in the context of I/R injury needs to be further explored. In this study, we investigate the short-and long-term effects of SAC/VAL administration in treating adult murine I/R injury both in vivo and in vitro. Our results verified that the application of SAC/VAL could reduce infarct size and suppress apoptosis and the inflammatory response in the acute phase post I/R. Long-term application of SAC/VAL for four weeks significantly improved ventricular function and reversed pathological ventricular remodeling. Mecha-nistically, SAC/VAL treatment induces the inhibition of the GSK3 beta-mediated NF-kappa B pathway through synergis-tically blocking angiotensin 1 receptor (AT1R) and activating natriuretic peptide receptor (NPR). In summary, we reported the therapeutic role of SAC/VAL in regulating the GSK3 beta/NF-kappa B signaling pathway to suppress the inflammatory response and apoptosis, thereby reducing cardiac dysfunction and remodeling post I/R.