The Study On The Protective Role Of Remote Ischemic Postconditioning Mediated HIF-1? And TRPM7 In Hypoxic Cardiomyocytes

Early reperfusion after ischemia is very important for reducing myocardial injury,but reperfusion can induce reperfusion injury(IR)even myocardial cell apoptosis.The time characteristics of reperfusion injury make the clinical application of ischemic preconditioning difficult.In 2003,Zhao ZQ suggested the concept of"postconditioning",that is,a series of transient reperfusion-ischemia before the complete recovery of ischemic myocardium,thus protecting the ischemic myocardium.In vitro or in vivo animal experiments,the factors involved in the treatment of myocardial protection include:1,the activation of endogenous adenosine receptor;2,potassium ATP channel opening;3,reperfusion injury remedial kinase(PI3K/AKT/e NOS)signaling pathway;4,intracellular and mitochondrial calcium overload 5,The opening of mitochondrial transpermeable transport micropores."Remote postconditioning"is proposed on the basis of post-processing research that transient ischemia reperfusion is carried out on the other organ before the onset of myocardial ischemia and reperfusion,thus initiating the endogenous protective mechanism of the body.In 2005,Kerendi first studied the effect of Remote postconditioning.The results showed that the area of myocardial infarction could be reduced by 50%in the distant post treatment.Its protective effect may be associated with the increase of endogenous adenosine secretion after transient ischemia-reperfusion,and the results of activation of adenosine receptor related to.Tsubota are similar to that of Kerendi.In 2007,Andreka et al showed that remote postconditioning reduced infarct size by 22%-47%.Gritsopoulos used the rabbit acute myocardial infarction model,which confirmed that far post conditioning was more effective than routine treatment in reducing infarct size.This protective effect may be associated with e NOS activation.Distant post-treatment can reduce myocardial ischemia and reperfusion injury to varying degrees.However,this kind of research is still in the early stage.Few research reports have been reported.The mechanism of its myocardial protection is still unclear,but it is suggested that remote postconditioning may be a more promising myocardial protective measure than conventional postconditioning.Although remote preconditioning and remote postconditioning can achieve myocardial protection,the clinical application is still difficult.The results of Hausenloy's clinical study showed that the distant ischemic preconditioning of the lower limbs did not protect the patients with coronary artery bypass grafting,which was far from the animal experimental results.Wu et al have found that hypercholesterolemia can eliminate the protective effect of postconditioning on the myocardium,and the Kieran review of the clinical application of preconditioning explicitly mentioned that the presence of hypercholesterolemia,such as hypercholesterolemia,could significantly affect the protective effect of the myocardium.All these studies suggest that there is difference between ischemic preconditioning and postconditioning in pathological condition.Therefore,it is the key point for PC/Post C/RPost C to detect the complications of hypercholesterolemia and so on.Objective:To investigate the protective effect of HIF-1?and TRPM7 on myocardium and its mechanism.Methods:This study was divided into two parts:Part I.The protective effect of hypoxia inducible factor-1?(HIF-1?)on myocardium in hyperlipidemia rabbit remote ischemic postconditioning;Part?.Ischemic postconditioning increased the inhibitory effect of mir-22-3p on TRPM7 and the protective effect of TRPM7 on H9c2 cardiomyocytes.Part I is in vivo organ experiment.The myocardial protective effect of HIF-1?in remote postconditioning was observed in rabbits.Part?is cell experiment.We used H9C2 cardiomyocytes as the research object to observe the role of TRPM7 in the protection or injury of H9C2 cardiomyocytes during hypoxia reoxygenation by constructing TRPM7 interference expression vector and knocking down mirna-22-3p to increase TRPM7 expression.Results:Part I:1.The results of blood biochemical indexes showed that HIF-1?sensitizer could play an effective role in myocardial protection;2.Animal experiments showed that ischemic postconditioning could promote the activation of PI3K/Akt/e NOS/HIF-1?pathway.Part?:1.Hypoxia postconditioning promotes the expression of HIF-1?in H9C2 and inhibits the expression of TRPM7;2.Hypoxic postconditioning is positively correlated with mir-22-3p,which can directly target TRPM7 gene and regulate its m RNA expression;3.Hypoxic postconditioning reduces TRPM7 expression by targeting TRPM7 with mir-22-3p.Conclusion:Part I:in hyperlipidemia rabbit model,1,HIF-1?enhancer dmog+two kinds of distal myocardial ischemia(lung and lower limb)postconditioning can reduce the area of myocardial infarction induced by reperfusion.2.Myocardial ischemic distal postconditioning can reduce the high plasma creatine kinase activity induced by reperfusion.3.Myocardial ischemic distal postconditioning can reduce myocardial cell apoptosis induced by reperfusion.4.At the same time,PI3K/Akt/e NOS/HIF-1?pathway was activated to protect myocardium.Part?:1.Ischemic postconditioning may inhibit the expression of TRPM7through mir-22-3p,thus playing a protective role in the process of myocardial ischemia-reperfusion injury.2.HIF1-?can be used as an indicator for H9C2cardiomyocytes to characterize the success of hypoxia model construction and interference treatment.3.TRPM7 interference vector may promote cell survival,inhibit cardiomyocyte apoptosis,maintain cell Ca²⁺concentration,and play the role of reperfusion protection of H9C2 cardiomyocytes by inhibiting the expression of TRPM7.