Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) is a serine protease involved
in cholesterol homeostasis. After binding to the complex low-density lipoprotein
(LDL)-receptor, PCSK9 induces its intracellular degradation, thus reducing serum LDL clearance.
PCSK9 is mainly secreted by the liver, but it is also expressed to a lesser extent in other
organs. Apart from the well-known activity concerning hepatic LDL receptor-mediated pathway,
PCSK9 has been supposed to potentially interfere with vascular inflammation in atherogenesis.
Vascular smooth muscle cells have been demonstrated to produce higher amounts of
PCSK9 as compared to endothelial cells especially in an inflammatory microenvironment.
Low shear stress regions increase PCSK9 expression within SMCs, while higher shear stress
gradually reduced PCSK9 expression. Moreover, a crosstalk between PCSK9 and reactive
oxygen species has been also described. Oxidized LDL was shown to up regulate the expression
of PCKS9 by influencing dose-dependently the secretion of interleukin (IL)-1α, IL-6, and
tumor necrosis factor-α. After the identification of gene loss-of-function mutations and no detectable
circulating protein levels, PCSK9 has attracted a great interest as an effective target
for cholesterol-lowering therapies. Different strategies have been implemented to block the
effects of both intracellular and circulating PCSK9. In particular, monoclonal antibodies represent
the most promising approach and two of these, alirocumab and evolocumab, have been
approved for clinical use in patients affected by familial hypercholesterolemia with encouraging
results. In the next future, the improvement of the knowledge of the “pleiotropic” effects
of PCSK9 inhibitors might unveil therapeutic potential on cardiovascular outcome independently
on the cholesterol lowering activity.