PCSK9 modulates the Wnt/beta-catenin signaling pathway in myocardial ischemia/reperfusion injury

Abstract Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein that affects cholesterol homeostasis. Recent research has found PCSK9 various effects on the heart are unrelated to LDL regulation. The Wnt/β-catenin signaling pathway plays crucial role during development, and it re-activated in response cardiac injury. Low-density lipoprotein receptor-related proteins 5 (LRP5) act as co-receptors of Wnt ligands indispensable for signal transduction. However, not fully elucidated whether other members LDLR-superfamily may be targets PCSK9. Purpose This study aimed determine if LRP5 target, association between signaling, elucidate its effect myocardial infarction patients with ischemic cardiomyopathy. Methods expression Lrp5, phospho-β-catenin, total β-catenin was evaluated by western blot analysis, overexpressed were tested under normoxia, hypoxia, or hypoxia/re-oxygenation (H/R) mouse cardiomyocytes (HL-1). transcriptional activity assessed using TOP-Flash/FOP-Flash luciferase reporter assay. In addition, impact downstream quantitative real-time polymerase chain reaction. To examine regulates injury vivo, we subjected transgenic mice cardiac-specific overexpression (PCSK9 TG) wild-type (WT) either sham surgery ischemia/reperfusion (I/R) surgery. Results Under hypoxic conditions, pathway-related genes downregulated HL-1 cells, evidenced lower Lrp5 active phospho-β-catenin levels (0.5-fold, n=3, p<0.01). After H/R, Wnt/β-catenin-related recovered (1.5-fold, p<0.01) control group but group. assay results, inhibited recovery after contrast Furthermore, mRNA Axin2, Cyclin D1, which targets, down-regulated hypoxia H/R did recover cells. I/R model, overall signaling-related TG compared WT Conclusions These results indicated regulation closely associated play damaged cardiomyocytes. It suggests could therapeutic target Funding Acknowledgement Type funding sources: None.