| Acute myocardial infarction is a leading cause of human death worldwide. In the clinic, restoration of blood flow is the most effective way for the myocardium to prevent eventual necrosis. However, myocardial ischemia reperfusion (IR) injuries such as arrhythmias, stunning, and microvascular damage are also found when the blood flow is restored.Two major factors, namely oxidative stress and inflammatory response, play vital roles in the processes of necrosis and apoptosis, which are also involved in the pathogenesis of IR injury. Oxidative stress is usually associated with the formation of reactive oxygen species (ROS), which often triggers a cytotoxic cascade during which various downstream targets are activated successively, leading to inflammation and lipid peroxidation. Strengthening the antioxidant defense and inhibiting the apoptotic pathway may be important for reducing myocardial IR damage.CAPE, a small, flavonoid-like compound isolated from honeybee propolis, possesses high anti-inflammatory, antioxidant, free radical scavenging, and anti-platelet aggregation activity and has protective effects against IR injury. In our previous study, a series of CAPE derivatives were designed and synthesized. Among these derivatives, p-nitro caffeic acid phenethyl ester possessed the highest activity against platelet aggregation and the highest capability to increase the white blood cell (WBC) count, the spleen index, the thymus index and nitric oxide production.Several drugs used for treating cardiac disease, such as nifedipine and imodipine, contain unsaturated p-nitro and phenyl moieties. In view of the similarity of the structure between these drugs and CAPE-NO2, we hypothesized that this new derivative could provide increased protection against myocardial IR injury in vivo. In the present study, a rat model was employed to investigate the protective effects and mechanism of CAPE-NO2 on myocardial IR-induced injury in rat heart.Myocardial ischemia reperfusion (IR) causes a series of cardiomyocyte dysfunction including apoptosis and necrosis. The purpose of this study was to investigate the possible cardio-protective effects of CAPE-NO2 on myocardialIR-induced injury in vivo. In a rat model, to induce myocardial IR, the left anterior descending coronary artery (LAD) was occluded for 30 min followed by reperfusion for 2hrs.5 min before the occlusion, the rats were given either sham treatment (the sham group and the I/R control group) or drugs (the CAPE group and the CAPE-NO2 group). Briefly, the left anterior descending coronary artery (LAD) was ligated using a 6-0 silk suture. Additionally, a medical latex tube (inner diameter,1.5 mm) was placed between the ligature and LAD. Myocardial ischemia was induced by compressing the LAD by tightening the ligature around the latex tube. Significant ECG changes, including elevation of the ST segment and widening of the QRS complex, indicated a successful coronary occlusion. After 30 min of ischemia, the latex tube was removed to restore the coronary circulation. The sham group underwent the same procedures, except that the silk suture was left untied.Myocardial IR-induced injury is characterized by a significant increase in the level of myocardial enzymes, such as a significant decrease in myocardial antioxidants, such as catalase (CAT), total superoxide dismutase (T-SOD) and glutathione-peroxidase (GSH-Px). Pretreatment of CAPE-NO2 significantly ameliorated these changes, and decreased infarct size (10.32 ± 3.8% in the CAPE-NO2 group vs.35.65 ± 5.4% in the I/R control group). Moreover, western blotting analysis indicated pretreatment with CAPE-NO2 down-regulated myocardial IR-induced protein expressions of Bax, cleaved-caspase-3, P38 and the Bax/Bcl-2 ratio. CAPE-NO2 also up-regulated myocardial IR-induced expressions of Bcl-2, PI3K, p-Akt and mTOR. In summary, our data indicate that CAPE-NO2 showed better cardio-protective effects than CAPE, and CAPE-NO2 may represent a novel approach to cardioprotection therapeutics. |
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