The Effects of Progranulin in a Rat Model of Acute Myocardial Ischemia/Reperfusion are Mediated by Activation of the P13K/Akt Signaling Pathway

Abstract

BackgroundProgranulin is an adipokine, encoded by the progranulin (GRN) gene. Progranulin is expressed in atherosclerosis, but its effects in cardiac ischemia and reperfusion injury are unknown. Therefore, this study aimed to investigate the effects of progranulin in a rat model of acute myocardial ischemia/reperfusion (MI/R) injury in vivo.Material/MethodsThe model of acute MI/R injury was established in male Wistar rats by ligation of the left anterior descending (LAD) coronary artery for 30 minutes and reperfusion for 60 minutes. Before modeling, one group was treated with progranulin (0.03 μg/kg), and one group was treated with the P13K/Akt inhibitor, LY294002 (3 mg/kg). Left ventricular function (LV) was monitored, including the LV systolic pressure (LVSP), LV end-diastolic pressure (LVEDP), and changes in LV pressure. At the end of the study, blood and myocardial tissue were examined. Cardiac biochemical markers, histopathology, gene expression, and apoptosis were analyzed.ResultsProgranulin improved cardiac function following acute MI/R injury and significantly improved recovery of cardiac contractility and LVSP. Progranulin significantly reduced myocyte apoptosis, inflammation, and tissue edema, and was highly expressed in cardiac tissue following MI/R injury. The cardioprotective effect of progranulin was reduced by blocking the P13K/Akt signaling pathway.ConclusionsIn the rat model of acute MI/R injury, progranulin had a protective effect on cardiac function and morphology, associated with activation of the P13K/Akt signaling pathway. The mechanisms of the anti-apoptotic, anti-inflammatory, and inotropic effects of progranulin in the setting of acute MI/R injury require further in vivo studies.

Bioinformatics and Experimental Analyses Reveal NFIC as an Upstream Transcriptional Regulator for Ischemic Cardiomyopathy

“…The PI3K-Akt signaling pathway is enriched in both DAVID and WEAT KEGG analyses. Previous studies have shown that the activation of the P13K/Akt signaling pathway enhances the cardioprotective effect of progranulin in the rat model of acute MI/R injury [ 37 ]. In our study, several genes ( DDIT4 , MYC , CSF3 , TNC , EIF4E1B , PCK2 , and BDNF ) belonging to the P13K/Akt signaling pathway were downregulated in ICM, indicating the potential diagnostic and therapeutic targets of ICM.…”

Effects of progranulin on the pathological conditions in experimental myocardial infarction model

“…Initial injury provoked by MI associates with subsequent cardiac dysfunction and high mortality 39,40 . A recent study has reported that www.nature.com/scientificreports/ administration of recombinant human progranulin significantly improved cardiac function through activation of PI3K/Akt signaling pathway, 30 min after ischemia followed by 60 min reperfusion in rats 18 . Therefore, in our study, protective effects of progranulin on myocardial I/R injury might be associated with initial activation of PI3K/Akt.…”

“…Progranulin gene mutations have been identified in the pathogenesis of frontotemporal lobar degeneration associated with the accumulation of TAR DNA-binding protein 43 (TDP-43) 17 . Previous reports have shown that progranulin protects against I/R injury in the heart, brain and kidney 18 – 20 . In our previous report, the administration of recombinant progranulin also attenuated neuronal injury by inhibiting neutrophil recruitment in a focal cerebral I/R injury murine model 19 .…”

“…In our previous report, the administration of recombinant progranulin also attenuated neuronal injury by inhibiting neutrophil recruitment in a focal cerebral I/R injury murine model 19 . It recently has been reported that progranulin protects cardiac dysfunction in the early phase after myocardial I/R injury 18 . However, it is still not fully understood how progranulin is involved in ischemic lesion and cardiac remodeling after AMI.…”

Signaling pathways of inflammation in myocardial ischemia/reperfusion injury

“…Phosphoinositide-3 kinase (PI3K) is a key regulator of serine/threonine kinase (Akt) [81] , which in turn downregulate the expression of IκB (Figure 2) [82] . A variety of molecules, including TRIM59 [83] , flavonoids [84] , SH2B1 [85] , progranulin [86] , epigallocatechin [87] , gypenoside [88] , and berberine [89] , have been shown to attenuate inflammation in MI/RI via activating the PI3K/Akt signaling pathway. Studies have implicated the PI3K/Akt signaling pathway in the anti-inflammatory effects of baicalin [90] and 6-gingerol [91] in MI/RI.…”