LipoxinA₄ attenuates myocardial ischemia reperfusion injury via a mechanism related to downregulation of GRP-78 and caspase-12 in rats

This study aims to determine the effect of Lipoxin (LX)A₄ on myocardial ischemia reperfusion injury (MIRI) in rats and the related molecular mechanisms. Male SD rats were divided into six groups. The sham operation groups (groups C1, C2) were injected with 2 ml/kg normal saline before and after coronary artery threading, respectively. The MIRI group (groups I/R1, I/R2) were injected with normal saline before and after MIRI, respectively. The LXA₄ groups (groups LX1, LX2) were injected with LXA₄ before and after MIRI treatment, respectively. The hematoxylin–eosin staining and ultrastructural changes of cardiac muscle were observed. The serum levels of interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF) α and cardiac troponin I (cTnI) were measured before open-chest operation and at the end of the experiment. The mRNA and protein levels of GRP-78 and caspase-12 were determined in each group. The myocardial cell apoptosis, myeloperoxidase (MPO), superoxide dismutase (SOD), and malondialdehyde (MDA) contents were detected. The mRNA and protein levels of GRP-78 and caspase-12, the apoptosis, the serum IL-1β, IL-6, IL-10, TNF-α, and cTnI concentrations, MPO, SOD, MDA contents were significantly increased in groups I/R1, I/R2, LX1, and LX2 compared with those in groups C1 and C2 (P < 0.05). The mRNA and protein expression levels of GRP-78 and caspase-12 in groups LX1 and LX2 were lower than those in groups I/R1 and I/R2. Compared with group I/R1 and I/R2, the myocardial neutrophil infiltration and ultrastructure damage were significantly less in groups LX1 and LX2. GRP-78 and IL-10 are expressed both extracellularly and intracellularly, but are mainly expressed in the cytoplasms. In the absence of MIRI, LXA₄ has no detectable effect on GRP-78 and caspase-12 expression. Before and after MIRI, application of LXA₄ significantly inhibits neutrophil activation, and attenuates myocardial inflammatory injury and oxidative stress. LXA₄ downregulates the mRNA and protein expression of GRP-78 and caspase-12. LXA₄ could play a role in myocardial protection via a mechanism related to downregulation of GRP-78 and caspase-12, and inhibition of apoptosis.