New role of PCSK9 in atherosclerotic inflammation promotion involving the TLR4/NF-κB pathway

PCSK9: A novel inflammation modulator in atherosclerosis?

“…We demonstrated that knockdown of PCSK9 inhibits the oxLDLinduced inflammatory response in macrophages, whereas its overexpression has an opposite effect (Tang et al, 2017). Similar results were obtained in LPS-treated mouse peritoneal macrophages (MPM) from mPCSK9 −/− mice and human PCSK9 transgenic (hPCSK9tg)/ apoE −/− mice .…”

“…Decreased TNF-α, IL-1β, and MCP-1 expression (Tang et al, 2017) OxLDL-stimulated dendritic cells with siR-PCSK9 treatment Decreased TNF-α, IL-1β, and IL-6 production (Liu & Frostegard, 2018) PCSK9 inhibition C57BL/6 mice with CLP treated with PCSK9-blocking antibody Decreased plasma TNF-α, IL-6, IL-10, MCP-1, and MIP-2 levels (Walley et al, 2014) PCSK9 overexpression PCSK9 Tg mice with CLP Increased plasma IL-6 levels Increased lung and liver inflammation (Dwivedi et al, 2016) LPS-stimulated MPM from hPCSK9tg/ apoE −/− mice Increased TNF-α and IL-1β expression Reduced IL-10 and Arg1 expression OxLDL-stimulated raw264.7 with LV-PCSK9 transfection Increased TNF-α, IL-1β, and MCP-1 expression (Tang et al, 2017) Increased plasma TNF-α, IL-6, IL-8, and MCP-1 levels (Walley et al, 2014) Note. CLP: cecal ligation and puncture; IL: interleukin; GOF: gain-of-function; LPS: lipopolysaccharide; LV: lentivirus; LOF: loss-of-function; MPM: mouse peritoneal macrophages; PCSK9: proprotein convertase subtilisin/kexin 9; TNF-α: tumor necrosis factor alpha.…”

Research progress on alternative non-classical mechanisms of PCSK9 in atherosclerosis in patients with and without diabetes

“…These findings indicate that PCSK9 siRNA suppressed the release of inflammatory cytokines in ox-LDL-stimulated macrophages through inhibiting IκBα degradation and NF-κB nuclear translocation, thus providing protection against inflammation. Tang et al [55] further investigated the pro-inflammatory effect of PCSK9. The authors found that the expression level of PCSK9 was increased in atherosclerotic plaques and that PCSK9-silenced mice exhibited fewer aortic atherosclerotic plaques, as well as decreased expression of vascular inflammation regulators, such as IL-1β, TNFα, monocyte chemo-attractant protein 1 (MCP-1), TLR4, and NF-κB, in the lesions [55].…”

Research update for articles published in EJCI in 2016

“…58 However, PCSK9 was suggested to potentially induce pleiotropic activities including a negative control on the inflammatory response. 59 In addition, PCSK9 is constitutively expressed within the brain and may affect neuronal development and apoptosis. 60 The lack of knowledge in PCSK9-related pathophysiology may partially explain the controversial effects of PCSK9 inhibitors on postischaemic inflammatory response.…”