Oxycodone attenuates lipopolysaccharide-induced myocardial injury by
inhibiting inflammation, oxidation and pyroptosis via Nrf2/HO-1
signaling pathway
Abstract
Myocardial injury and cardiovascular dysfunction are the most common
complications in patients with sepsis, and effective therapeutic
candidate is still lacking. This study aims to investigate the
protective effect of oxycodone in the myocardial injury in
lipopolysaccharide-induced sepsis and its related signaling pathways.
Wildtype and Nrf2-knockout mice, as well as H9c2 cardiomyocytes culture
treated with LPS were used as models of septic myocardial injury. In
vitro model showed that oxycodone protected the cells from pyroptosis
induced by LPS. In vivo model showed oxycodone pretreatment
significantly attenuated myocardial pathological damage and improved
cardiac function with increased ejection fraction (EF) and fractional
shortening (FS) as well as decreased cardiac troponin I (cTnI), creatine
kinase isoenzymes MB (CK-MB). Oxycodone also reduced the levels of
inflammatory factors and oxidative stress damage induced by LPS, which
involves pyroptosis-related proteins including the NLRP3, Caspase-1,
ASC, and GSDMD. These changes were mediated by Nrf2 and HO-1 because
Nrf2-knockout mice or Nrf2 knockdown in H9c2 cells significantly
reversed the beneficial effect of oxycodone on oxidative stress,
inflammatory responses and NLRP3-mediated pyroptosis. Our findings
proved that oxycodone therapy reduces LPS -induced myocardial injury by
suppressing NLRP3-mediated pyroptosis via the Nrf2/HO-1 signaling
pathway in vivo and in vitro.