Simvastatin relieves myocardial ischemia/reperfusion injury in rats through hedgehog signaling pathway.

Abstract

The aim of this study was to explore the effect of simvastatin (Sim) on myocardial ischemia/reperfusion (I/R) injury in rats and to elucidate the possible underlying mechanism. Our findings might help to provide a certain reference for the clinical prevention and treatment of myocardial I/R injury. A total of 60 male Sprague-Dawley (SD) rats were randomized into three groups using a random number table, including: Sham group (n=20), I/R group (n=20) and I/R + Sim group (n=20). The I/R injury model was successfully established in rats via ligation of the left anterior descending coronary artery (LAD), followed by reperfusion. Before operation, the rats in I/R + Sim group were administered with Sim at 10 mg/kg/d through oral gavage for 7 d. Cardiac ejection fraction (EF) (%) and fractional shortening (FS) (%) of rats in each group were detected using echocardiography. 2,3,5-triphenyltetrazolium chloride (TTC) staining was performed to measure the myocardial infarction (MI) area in each group. Collagen deposition in myocardial tissues of rats in each group was detected by Masson's trichrome staining. The apoptosis level of myocardial cells and fibroblasts in myocardial tissues of rats in each group were evaluated via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. The level of reactive oxygen species (ROS) in myocardial tissues of rats in each group was determined using fluorescent probes. Reverse Transcription-Polymerase Chain Reaction (RT-PCR) was conducted to measure the expression levels of pro-inflammatory cytokines interleukin (IL)-1β and monocyte chemoattractant protein-1 (MCP-1) in myocardial tissues of rats in each group. Furthermore, the effects of Sim on the hedgehog signaling pathway-associated proteins were detected using Western blotting. Sim significantly alleviated I/R-induced cardiac dysfunction in rats and increased EF (%) and FS (%) (p<0.05). Meanwhile, it also evidently mitigated the MI caused by I/R and reduced the infarction area (p<0.05). According to the Masson's trichrome staining results, I/R + Sim group exhibited remarkably declined myocardial interstitial collagen deposition compared with I/R group (p<0.05). ROS-sensitive fluorescent staining showed that Sim notably reversed the increase of ROS expression and the decrease of myocardial oxidative stress induced by I/R (p<0.05). Finally, Western blotting results revealed that Sim dramatically restrained the protein expressions of sonic hedgehog (SHH), patched 1 (PTC1) and glioma-associated oncogene homolog 1 (GLI1) (p<0.05). Sim can significantly relieve myocardial I/R injury in rats. The possible underlying mechanism may be related to its inhibition on the hedgehog signaling pathway.