| BACKGROUNDAcute myocardial infarction(AMI)is a common heart disease that can lead to irreversible myocardial necrosis due to long-term ischemia and hypoxia,posing a health threat to humans,especially the elderly.In order to protect ischemic myocardium,timely reperfusion is crucial,but myocardial ischemia-reperfusion(I/R)is an extremely complex pathophysiological process that can cause severe acute and chronic myocardial injury.At present,it is believed that the central element of myocardial ischemia-reperfusion protection is mitochondria,especially mitochondrial permeability converting protein(mPTP),which plays an important role in regulating mitochondrial function and cell apoptosis.In addition,lipid overload during myocardial ischemia,hypoxia,and reperfusion can also cause damage to mitochondria.Therefore,reducing lipid toxicity during myocardial ischemia-reperfusion may be a new treatment strategy.CD36 is a transmembrane glycoprotein belonging to the scavenger receptor family,mainly mediating the transmembrane transport of long-chain fatty acids to regulate lipid homeostasis and energy balance.CD36 plays an important role in myocardial ischemia-reperfusion injury.It affects the function and structure of mitochondria by regulating the fatty acid uptake and metabolism of myocardial cells.The expression and membrane distribution of CD36 are regulated by the PI3K/Akt signaling pathway,thereby inhibiting myocardial cell apoptosis,inflammatory response,and oxidative stress.Dexmedetomidine(DEX)is a selective drug α2 receptor agonists can protect multiple organs from ischemia-reperfusion injury.Dexmetomidine can activate the PI3K/Akt signaling pathway,but there is no clear evidence to determineMETHODSForty eight male rats belonged to SD were randomly divided into four groups designed as Sham group,MI/R group,DEX group and DEX+LY294002 group(DEX+LY group).Except Sham group,the rats in other groups were subjected to myocardial ischemia for 30 min and reperfusion for 120 min to establish the I/R injury model.DEX100 ug/kg was intraperitoneally injected before ischemia in DEX group.DEX100 ug/kg and PI3K inhibitor LY294002 0.3 mg/kg were intraperitoneally injected at 30 min before ischemia in DEX+LY group.Limb lead electrocardiogram was continuously monitored during the experiment.After reperfusion,the hearts of rats were quickly removed,and myocardial infarction size was detected with TTC staining.The expression of PI3K,p-PI3K,Akt,p-Akt,FoxO1,p-FoxO1,and CD36 proteins in the ischemic myocardium were determined with western blotting.The expression of CD36 protein in the ischemic myocardium was detected by Immunofluorescence.GPO-PAP method was used to detect the content of TNF-α in ischemic lesions.RESULTS(1)The model of myocardial ischemia-reperfusionDuring the ischemic period,the color of the myocardial surface turned white or cyanosis,the vitality was weakened,and the electrocardiogram showed ST segment elevation.After reperfusion,the color of the myocardial surface turned ruddy,the vitality increased,and the electrocardiogram showed ST-segment resolution.(2)The heart rate variabilityCompared with the Sham group,the heart rate variability in the MI/R group,DEX group and DEX+LY group was significantly increased(P<0.01).Compared with the MI/R group,the heart rate variability was significantly increased in the DEX group(P<0.05).(3)The changes of ECG ST-segmentThe changes of ECG ST-segment during MI/R in DEX group and DEX+LY group showed different degrees of ST-segment elevation.Compared with the Sham group,the ECG ST segment was significantly elevated in other groups(P<0.05).Compared with MI/R group,the ST segment of DEX group decreased significantly(P<0.05),but decreased in the DEX+LY group and there was no significant change(P>0.05).(4)The difference of myocardial infarction sizeThe difference of myocardial infarction size in Sham group was normal by TTC staining,which meaned there was no myocardial infarction,while the myocardial tissue in MI/R group,DEX group and DEX+LY group showed different degrees of pale infarction.When compared with the Sham group,the infarct size in the MI/R group was biggest(P<0.01).Compared with the MI/R group,the myocardial infarct size was significantly declined in the DEX group(P<0.05),while the myocardial infarct size was declined but not significantly in the DEX+LY group(P>0.05).(5)The expression of target proteinCompared with Sham group,the content of p-PI3K、p-FoxOlin MI/R group and DEX group was significantly increased(P<0.05;P<0.01),and the content of p-Akt in DEX group was greatly declined(P<0.05).Compared with the MI/R group,the content of p-PI3K、p-Akt and p-FoxO1 in the DEX group was significantly growed(P<0.05),while that in the DEX+LY group was significantly decreased when in comparsion with DEX group(P<0.01).Compared with the Sham group,the content of CD36 significantly descended in the DEX group(P<0.05).In comparsion with MI/R group,the content of CD36 decreased in DEX group and DEX+LY group,but no significant difference was found(P>0.05).(6)the expression of CD36 immunofluorescenceIn comparsion with Sham group,the expression of CD36 immunofluorescence in myocardial ischemia was significantly decreased in DEX group(P<0.05),but there was no any significance in the other groups.(7)The content of triglycerideIn comparsion with Sham group,it was significantly increased in MI/R group about the content of triglyceride(P<0.05),but there was no any significance in the other groups.(8)The content of TNF-αIn comparsion with Sham group,it was significantly increased in MI/R group,DEX group and DEX+LY group with respect to the content of TNF-α in myocardial ischemia(P<0.01).Compared with MI/R group,the content of TNF-α in myocardial tissue of DEX group decreased significantly(P<0.01).In contrast to DEX group,the content of TNF-α in myocardial tissue was significantly increased in DEX+LY group(P<0.05).CONCLUDSIONS(1)There were significant reduction for heart rate variability,ECG changes,infarct size and TNF-α in the myocardial ischemia-reperfusion model after using DEX by intraperitoneal injection.(2)DEX preconditioning may reduce the expression of CD36 protein and then protect myocardium during myocardial I/R through activating PI3K/Akt pathway and phosphorylating FoxO1 subsequently. |
