Targeting myeloid-PCSK9 enhancing cardio-protection beyond LDL cholesterol-lowering

Circulating Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) levels, known for regulating plasma cholesterol by degrading LDL receptors, correlate with acute myocardial infarction (AMI) risk. Recent studies suggest that PCSK9 improves cardiac function beyond LDL cholesterol levels after cardiac ischemic injury, but the precise role of PCSK9 in this process is not clarified yet. Our study reveals that PCSK9 deficiency induces heterogeneous changes in myeloid cells and macrophages, potentially protecting the heart in AMI regardless of LDL cholesterol homeostasis. Single-cell RNA sequencing identifies PCSK9-dependent cardiac macrophages (PDCMs) as reparative macrophages enriched in activator protein-1 (AP-1) transcription factor (TF)-related pathways. PDCMs enhance VEGF-C secretion and activate Akt signalling in cardiac endothelial cells, improving cardiac remodelling. Indeed, PCSK9 inhibitor-treated coronary artery disease (CAD) patients show increased myeloid cells with PDCM-like features. In sum, targeting myeloid-PCSK9 may offer cardio-protective effects through increased AP-1 activity and VEGF-C expression, providing a novel approach to prevent cardiac dysfunction in AMI.