Local effects of human PCSK9 on the atherosclerotic lesion

Abstract

Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) promotes atherosclerosis by increasing low-density lipoprotein (LDL) cholesterol levels through degradation of hepatic LDL receptors (LDLR). Studies have described the systemic effects of PCSK9 on atherosclerosis, but whether PCSK9 has local and direct effects on the plaque in unknown. To study the local effect of human PCSK9 (hPCSK9) on atherosclerotic lesion composition independently of changes in serum cholesterol levels we generated chimeric mice expressing hPCSK9 exclusively from macrophages using marrow from hPCSK9 transgenic (hPCSK9tg) mice transplanted into apoE−/− and LDLR−/− mice, which were then placed on a high fat diet for 8 wk. We further characterized the effect of hPCSK9 expression on the inflammatory responses in the spleen and by mouse peritoneal macrophages (MPM) in vitro. We found that MPM from transgenic mice express both murine (m) Pcsk9 and hPCSK9 and that the latter reduces macrophage LDLR and LRP1 surface levels. hPCSK9 was detected in serum of mice transplanted with hPCSK9tg marrow, but did not influence lipid levels or atherosclerotic lesion size. However, marrow-derived PCSK9 progressively accumulated in lesions of apoE−/− recipient mice while increasing the infiltration of Ly6Chi inflammatory monocytes by 32% compared with controls. Expression of hPCSK9 also increased CD11b and Ly6Chi positive cell numbers in spleens of apoE−/− mice. In vitro, expression of hPCSK9 in LPS-stimulated macrophages increased mRNA levels of the pro-inflammatory markers Tnf and Il1b (40% and 45%, respectively) and suppressed those of the anti-inflammatory markers Il10 and Arg1 (30% and 44%, respectively). All PCSK9 effects were LDLR-dependent as PCSK9 protein was not detected in lesions of LDLR−/− recipient mice and did not affect macrophage or splenocyte inflammation. In conclusion, PCSK9 directly increases atherosclerotic lesion inflammation in an LDLR-dependent but cholesterol-independent mechanism, suggesting that therapeutic PCSK9 inhibition may have vascular benefits secondary to LDL reduction.

Suppressor of Cytokine Signaling-3 (SOCS-3) Induces Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Expression in Hepatic HepG2 Cell Line

“…Cells-In vivo evidence demonstrated the pivotal role of SOCS3 and STAT3 on lipid metabolism and SREBP-1 transcriptional activity (6,7,37). To verify that a similar response also occurs in our experimental model, we determined the mRNA levels of SREBP-1 target genes, such as FAS and SCD-1 and the levels of apoB.…”

Relationship between Plasma Proprotein Convertase Subtilisin/Kexin Type 9 and Estimated Glomerular Filtration Rate in the General Chinese Population

“…Therefore, the progression of kidney dysfunction may influence the expression or clearance of circulating PCSK9 levels, or in other words contribute to the change in plasma concentrations of PCSK9. Previous studies have reported that elevated PCSK9 concentrations are strongly associated with increased LDL-C levels and the development of atherosclerosis [8,16,18,19]. Consequently, PCSK9 inhibitors have become a novel therapeutic target for the therapy of hypercholesterolemia, which has been demonstrated to reduce the risk of cardiovascular disease [21,22].…”

“…Importantly, it is worth noting that disorders in lipid metabolism can also be observed in patients even in the early stage of kidney dysfunction [5,6]. Recently, proprotein convertase subtilisin/kexin type 9 (PCSK9), a novel protease, has been established as an important regulator in lipid metabolism by regulating low-density lipoprotein receptor expression [7,8] and its gain of mutation can result in elevated low-density lipoprotein cholesterol (LDL-C) and increased risk of CAD [8,9]. Hence, considering the effects of PCSK9 and status of kidney function on lipid metabolism, whether PCSK9 is involved in the different stages of the kidney dysfunction needs to be clinically studied.…”

Hypothesis

“…67 Recently, Giunzioni et al found that expression of human PCSK9 in LPS-stimulated macrophages increased mRNA levels of the proinflammatory markers, tumor necrosis factor a (TNF-a) and interleukin 1b (IL-1b), and suppressed those of the anti-inflammatory markers, IL-10 and Arg1 in vitro. 68 The PCSK9 is upregulated by oxLDL stimulation in a dosedependent manner in THP-1 (Human acute monocytic leukemia cell line)-derived macrophages. Small interfering RNA (siRNA)-mediated knockdown of PCSK9 suppresses the oxLDL-induced inflammatory cytokine expression.…”