sFRP3 inhibits WNT/β-catenin/PPAR δ pathway, triggers mitochondrial damage and pyroptosis in ischemia-reperfusion injury in senile hearts

Background Cardiac ischemia-reperfusion (IR) injury in elderly patients leads to severe secondary heart injury after reperfusion treatment of acute myocardial infarction. However, the mechanisms underlying such injury remain elusive. Method The model of myocardial ischemia-reperfusion in mice was established by operation. The HL-1 cells were used to create the hypoxia/ reoxygenation cardiomyocyte model, which were treated with over-expression of TXNIP, inhibition of TXNIP, inhibition of sFRP3, or inhibitor of β-catenin or PPAR δ. Mice in each group were injected with various adenoviruses through the tail vein. Then, cardiac function, myocardial infarction volume, cardiomyocyte pyroptosis, mitochondrial structure, intracellular reactive oxygen species, and the expression of related proteins were detected. Finally, the concentration of sFRP3, β -cantenin, PPAR δ, GSDMD, actived-Caspase-1, TXNIP, TRX 1, TRX 2, IL-1 β, and TNF- α in serum of the healthy elderly people, the elderly people with coronary atherosclerosis or the elderly patients who underwent emergency PCI for acute myocardial infarction were detected by ELISA. Result After cardiac ischemia/reperfusion, cardiac function was impaired, serum reactive oxygen species, inflammatory factors, and myocardial injury markers were significantly increased, myocardial pyroptosis cell and infarct volume were significantly increased, and mitochondrial structure and function were significantly impaired. Inhibition of sFRP3 can reverse these changes. However, the cardio- protective effect caused by sFRP3 inhibition was lost, when β-catenin/PPAR δ was inhibited or TXNIP was overexpressed. In contrast, the cardio-protective benefit caused by sFRP3 inhibition can be duplicated when TXNIP is inhibited. However, inhibition of β-catenin、PPAR δ or over-expression of TXNIP can reverse the cardio-protective effect caused by inhibition of sFRP3, and inhibition of TXNIP can reproduce the cardio-protective effect caused by inhibition of sFRP3. Conclusion Cardiac ischemia-reperfusion upregulates sFRP3, inhibits WNT/ β-catenin /PPAR δ pathway, and damages the structure and function of mitochondria, leading to the increase of ROS. Thus TXNIP is up-regulated, and pyroptosis is activated.