Proteomics and Lipidomics to unveil the contribution of PCSK9 beyond cholesterol lowering: a narrative review

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the key regulators of the low-density lipoprotein receptor (LDLR), can play a direct role in atheroma development. Although advances in the understandings of genetic PCSK9 polymorphisms have enabled to reveal the role of PCSK9 in the complex pathophysiology of cardiovascular diseases (CVDs), increasing lines of evidence support non-cholesterol-related processes mediated by PCSK9. Owing to major improvements in mass spectrometry-based technologies, multimarker proteomic and lipidomic panels hold the promise to identify novel lipids and proteins potentially related to PCSK9. Within this context, this narrative review aims to provide an overview of the most significant proteomics and lipidomics studies related to PCSK9 effects beyond cholesterol lowering. These approaches have enabled to unveil non-common targets of PCSK9, potentially leading to the development of novel statistical models for CVD risk prediction. Finally, in the era of precision medicine, we have reported the impact of PCSK9 on extracellular vesicles (EVs) composition, an effect that could contribute to an increased prothrombotic status in CVD patients. The possibility to modulate EVs release and cargo could help counteract the development and progression of the atherosclerotic process.

Keywords: atherosclerotic cardiovascular disease; extracellular vesicles; lipidomics; proprotein convertase subtilisin/kexin type 9; proteomics.

Figure 1

Role of PCSK9 in plaque progression. (A) Helical flow inhibits whereas low flow induces protein PCSK9 expression; (B) Schematic representation of the effect of PCSK9 on plaque progression fuelling. Compelling evidence implicates PCSK9 in plaque development. It is expressed in endothelial cells, vascular smooth muscle cells, and macrophages. In these latter, there is a stepwise increase in PCSK9 gene expression while transitioning from monocytes, to differentiating monocytes, to fully differentiated macrophages. Exposure to human recombinant PCSK9 up-regulates the mRNA expression of proinflammatory cytokines and chemokines (e.g., IL-1β, IL-6, TNF-α, CXCL2, and monocyte chemoattractant protein-1). CCL2, C-C motif chemokine ligand 2; ICAM-1, intercellular adhesion molecule 1; IL, interleukin; oxLDL, oxidized low-density lipoprotein; VCAM-1, vascular cell adhesion protein 1; VSMCs, vascular smooth muscle cells. The figure has been partially modified by permission of Oxford press (30).

Figure 2

Summary of the non-classic effects played by PCSK9 on various cell types in different organs: liver and lipid metabolism; brain; cardiomyocytes; vascular system with inflammation, atherosclerotic plaque formation and increased risk of thrombosis; CTRP9, C1q/tumour necrosis factor-related protein 9; ECs, endothelial cells; EVs, extracellular vesicles; LDL, low-density lipoprotein; LDL-C, LDL cholesterol; LDLR, low-density lipoprotein receptor; LRP1, low density lipoprotein receptor-related protein 1; M1, macrophages type 1; M2, macrophages type 2; VSMCs, vascular smooth muscle cells.