Effects Of Hyperglycemia On Expression Of TNNI3K,SCF And SDF-1 In Myocardium After Myocardial Ischemia/reperfusion Injury And Its Mechanisms

Background: Whether hyperglycemia(HG)alters the extent of MI/R injury is controversial.Most studies suggest that HG during acute myocardial infarction(AMI)is common and associated with increased risk of mortality and poor prognosis in patients with or without diabetes.In contrast,other studies demonstrated that hyperglycemia protected against ischemia induced myocardial damage on some conditions,and improved the recovery of heart function after MI/R.Cardiac troponin I interacting kinase(TNNI3K)is a cardiac-specific kinase that interacts specially with cardiac troponin I and belongs to MAPKKK family.TNNI3 K promotes cardiomyogenesis,enhances cardiac performance,and protects the myocardium from ischemic injury by suppressing p38/JNK-mediated apoptosis.TNNI3 K has been implicated in myocardial ischemia/reperfusion(MI/R)injury.Therefore,modulation of TNNI3 K activity would be a useful the rapeutic approach for ischemic cardiac disease.There were some studies about TNNI3 K as a target for the treatment of ischemic heart disease,but hardly any reports about the role of TNNI3 K in hyperglycemia with cardiac ischemic injury.Aims: 1.investigate the associations between TNNI3 K and familiar SCF or SDF-1 expression in the peri-infarcted myocardium after MI/R;2.investigate whether or not HG influences the expression of TNNI3 K,SCF and SDF-1 after MI/R and its associated mechanisms.Main methods: In vivo,mice were treated with citrate buffer or STZ to respectively construct control or hyperglycemia model.After that,mice were subjected to 45 min of left coronary artery ligation followed by 5 days of reperfusion to establish the model of MI/R injury.In vitro,we isolated and cultured the primary neonatal mice cardiomyocytes.The cells were incubated with high(HG,33 mM)or normal(LG,5.5 mM)glucose concentration medium and subsequently subjected to be anoxia and reoxygenation(A/R).Immunohistochemistry and Western blot analysis were used to detect the expression of TNNI3 K,SCF and SDF-1 protein and RT-qPCR was conducted for their mRNA expression.ELISA was used to detect the secretion of SCF and SDF-1 protein.Key results: 1.Immunohistochemistry uncovered that TNNI3 K,SCF and SDF-1 protein expression dramatically increased in the peri-infarcted myocardium after MI/R compared to corresponding sham group and infarcted myocardium.2.There was no significant difference in TNNI3K、SCF and SDF-1 mRNA and protein expression in sham group between normal(NG)and high glucose(HG)group.Total protein and mRNA expression of TNNI3 K dramatically increased in line with SCF and SDF-1 in the peri-infarcted myocardium of NG and HG group on Day 5 after MI/R compared to corresponding sham group,but HG simultaneously weakened their increase after MI/R.Meanwhile,in vitro,HG(33 mM)markedly decreased the TNNI3 K protein and mRNA expression in accord with SCF and SDF-1 compared to LG and according osmotic control group.3.Furthermore,phosphorylation of AKT and p38 were markedly inhibited on Day 5 after MI/R in the HG group compared to the NG group.At the same time,HG(33 mM)markedly decreased the AKT and p38 activation in cultured cardiomyocytes.Conclusion: 1.In the MI/R injury model,the expression of TNNI3 K in the peri-infarct myocardium increased synchronously with SCF and SDF-1,and the expression of these three genes was significantly increased on Day 5 after MI/R injury.2.HG simultaneously attenuated their increase after MI/R and A/R possibly via reduction of AKT and P38 MAPK activities.