Potential of PCSK9 as a new target for the management of LDL cholesterol
Research Reports in Clinical Cardiology
Potential of PCSK9 as a new target for the management of LDL cholesterol
0 Cardiovascular Department, Dyslipidemia Center, Azienda Ospedaliera Niguarda Cà Granda , Milan, italy
A large proportion of patients at high risk for cardiovascular disease continue to suffer from cardiovascular events despite current therapies. The need for additional therapies to lower the residual risk has led to research on new pharmacological approaches. The discovery of proteins regulating the activity of the low-density lipoprotein receptor has been a major breakthrough in the development of new cholesterol-lowering drugs. This review describes inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) as a promising treatment for familial hypercholesterolemia, especially the relatively good short-term safety of PCSK9 inhibitors. In particular, we focus on its additive effect with statins and its advantage as a monotherapy in statin-intolerant patients. The additional low-density lipoprotein cholesterol lowering obtained with PCSK9 inhibition will be able to reduce the additional risk, but its effect on cardiovascular events has to be evaluated in future studies.
Role of PCSK9
PCSK9 binds to the extracellular domain of the LDL receptor, ie, in the first epidermal
growth factor-like repeat homology domain,4 and is internalized along with the
receptor in the cells.5 The binding site for the LDL receptor is on the surface of the catalytic
domain containing Asp374.6 The C-terminal domain is not required for LDL receptor
binding, but is necessary for internalization of the complex.7 Interestingly, PCSK9 may
also bind to LDL receptor molecules intracellularly and regulate LDL receptor expression
Research Reports in Clinical Cardiology 2015:6 73–86 73
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on the cell surface.8 Annexin A2, a protein involved in diverse
cellular processes, binds to the C-terminal in the same way,
but inhibits degradation of the receptor, demonstrating that this
protein exerts an inhibitory function on PCSK9.9
Particularly important are the amino acid residues of the
first epidermal growth factor-like repeat homology domain
180 that coordinates the binding of calcium ions (Asp295, Glu296,
l-2u Asp310, Tyr315, and His306), which are responsible for the
-J21 specificity of the interaction with PCSK9.10 Some studies
on have demonstrated that PCSK9 locks the LDL receptor in
.377 an extended form, disrupting normal recycling of the LDL
.117 receptor by means of the cell surface.11 The PCSK9/LDL
.453 receptor complex moves to the endosomes by
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vo ity of PCSK9 to promote cellular degradation of the receptor
./dwww l.yone is not dependent on its catalytic activity, as demonstrated by
:/s su discovery of a mutation that prevents autocatalytic
processttp l
h na ing and is associated with low LDL cholesterol levels.13
from rsoe Subsequent studies investigated the molecular mechanism
by which PCSK9 influences metabolism of LDL
cholesterol.14 Beyond this activity, PCSK9 seems to be involved
in degradation of the very low-density lipoprotein (VLDL)
receptor and apolipoprotein E receptor 2,15 suggesting a role
in modulation of cellular functions. Recent intriguing studies
have identified a direct association with plasma triglycerides,
suggesting a potential effect of PCSK9 on triglyceride-rich
lipoproteins.16,17 Conf irming this observation, subjects
carrying a PCSK9 gain-of-function mutation showed a
three-fold elevation in apolipoprotein (apo)B100 production
rates compared with normal subjects.18 Chan et al found
that PCSK9 and apoC-III are inversely associated with the
catabolic rate of triglyceride-rich lipoprotein-apoB48,
suggesting a role of PCSK9 in the post-prandial coordination of
the catabolism of this lipoprotein.19 Studies in hepatocytes
found that PCSK9 binds to and reduces the intracellular
degradation of apoB100 independently of LDL receptor levels
and positively modulating the output of apoB.20 Contrasting
data show that PCSK9 levels do not correlate with VLDL
secretion or clearance in obese patients.21
Even if the liver is the main organ that regulates plasma
PCSK9 levels, oth (...truncated)