PCSK9 directly induces NF-kB mediated inflammation in human monocytes and endothelial cells

Abstract

therosclerotic cardiovascular diseases (ACVDs) are the leading cause of death world widely and excess low density lipoprotein cholesterol (LDL-C) is their most important causal risk factor. Proprotein convertase subtilisin/kesintype-9 (PCSK9) increases plasma levels of low-density lipoprotein cholesterol (LDL-C) through binding to the LDL receptors (LDLR) and mediating its lysosomal degradation on liver cells. PCSK9 also promotes atherosclerosis by increasing LDL-C levels through degradation of hepatic LDLR. Even though PCSK9 has been known to involve in atherosclerosis development, it has not been elucidated whether PCSK9 mediates local inflammation in the vessel wall, thereby directly effects on the plaque. To study the direct inflammatory effect of human PCSK9 (hPCSK9) on atherosclerotic lesion composition, we treated PCSK9 in the monocyte and endothelial cells. Interestingly, PCSK9 activates NF-kB and turns on the pro-inflammatory cytokines in the monocytes. Furthermore, treatment of PCSK9 increases the adhesion molecules

Integrins in the monocytes, and VCAM-1 and ICAM-1 in the endothelial cells. In mice, administration of PCSK9 (5ug/mouse

24 hour period) via the peritoneal route induced a significant accumulation of monocytes (26.6% increase) and macrophages (23.2% increase) into the peritoneal cavity. Taken together, we suggested that PCSK9 can directly induce inflammation through NF-kB activation, implying that PCSK9 directly accelerate atherosclerotic plaque progression by aggravating inflammatory conditions in the vessel wall through stimulating monocyte infiltration and activating endothelial cells.