Proprotein Convertase Subtilisin/Kexin Type 9 and Inflammation: An Updated Review

Abstract

The function of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9), a novel plasma protein, has mainly been involved in cholesterol metabolism in the liver, while, more interestingly, recent data have shown that PCSK9 also took part in the modulation of inflammation, which appeared to be another explanation for the reduction of cardiovascular risk by PCSK9 inhibition besides its significant effect on lowering lower-density lipoprotein cholesterol (LDL-C) concentration. Overall, a series of previous studies suggested an association of PCSK9 with inflammation. Firstly, PCSK9 is able to induce the secretion of proinflammatory cytokines in macrophages and in other various tissues and elevated serum PCSK9 levels could be observed in pro-inflammatory conditions, such as sepsis, acute coronary syndrome (ACS). Secondly, detailed signaling pathway studies indicated that PCSK9 positively regulated toll-like receptor 4 expression and inflammatory cytokines expression followed by nuclear factor-kappa B (NF-kB) activation, together with apoptosis and autophagy progression. Besides, PCSK9 enhanced and interacted with scavenger receptors (SRs) of inflammatory mediators like lectin-like oxidized-LDL receptor-1 (LOX-1) to promote inflammatory response. Additionally, several studies also suggested that the role of PCSK9 in atherogenesis was intertwined with inflammation and the interacting effect shown between PCSK9 and LOX-1 was involved in the inflammatory response of atherosclerosis. Finally, emerging clinical trials indicated that PCSK9 inhibitors could reduce more events in patients with ACS accompanied by increased inflammatory status, which might be involved in its attenuating impact on arterial plaque. Hence, further understanding of the relationship between PCSK9 and inflammation would be necessary to help prevent and manage the atherosclerotic cardiovascular disease (ASCVD) clinically. This review article will update the recent advances in the link of PCSK9 with inflammation.

Keywords: ASCVD; LOX-1; PCSK9 (proprotein convertase subtilisin kexin type 9); TLR4 (toll-like receptor 4); inflammation.

Figure 1

The regulation of on PCSK9 secretion. Pro-inflammatory factors, such as LPS, ox-LDL, TNF-α, and IL-1β induces the expression of PCSK9 in main sources for PCSK9 such as liver, kidney, small intestine, and in brain, heart, artery as well. LPS, lipopolysaccharide; oxLDL, oxidized low-density lipoprotein; TNF-α, tumor necrosis factor alpha; IL-1β, interleukin 1β; TLR4, toll-like receptor 4; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; PCSK9, proprotein convertase subtilisin/kexin Type 9.

Figure 2

PCSK9 mediate inflammation through enhancing expression of TLR4 and LOX. LOX can mainly increase uptake of ox-LDL, and TLR4 increase uptake of LPS. Then activation of NF-kB follows. Overall, activated NF-kB up-regulates expression of inflammatory cytokines, such as IL-6, IL-1, TNF-α, IFN- γ, and MCP-1. IL-1, interleukin 1; IL-6, interleukin 6; IFN-γ, interferon gamma; MCP-1, monocyte chemoattractant protein 1.

Figure 3

The effect of PCSK9 inhibition on vascular inflammation. PCSK9 inhibition could decrease the expression of main markers of vascular inflammation including M-CSF-1 and VEGF-A which leads to reduced ICAM-1 expression in endothelial cells and reduced infiltration of monocytes into the subendothelial layer. Moveover, PCSK9 inhibition reduces CCR2 expression and the inhibition of monocyte migration. Besides pro-inflammatory mediators, PCSK9 inhibitors may function through elevating anti-inflammatory cytokines such as IL-10. CCR2, C–C chemokine receptor Type 2; ICAM-1, intercellular adhesion molecule 1; LDL-C, low-density lipoprotein cholesterol; LOX-1, lectin-like oxidized LDL receptor-1; MCSF-1, major histocompatibility complex; oxLDL, oxidized low-density lipoprotein; SMCs, smooth muscle cells; VEGF-A, vascular endothelial growth factor A. The signal “→”indicates “promotes,” “⊣”indicates “inhibits”.