Potential of PCSK9 as a new target for the management of LDL cholesterol

Research Reports in Clinical Cardiology, Jul 2015

Potential of PCSK9 as a new target for the management of LDL cholesterol Guiliana Mombelli, Samuela Castelnuovo, Chiara PavanelloCardiovascular Department, Dyslipidemia Center, Azienda Ospedaliera Niguarda Cà Granda, Milan, ItalyAbstract: 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.Keywords: proprotein convertase subtilisin/kexin type 9, PCSK9, additional or replacement therapy to statins, statin intolerance, residual cardiovascular risk

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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 © 2015 Mombel i et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The ful terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php 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 clathrin-medi/ybom tahteisdbeinnddoincygtaogsiasi,nwsthLerDe Lth/LeDloLwerrecpeHptionrcrbeiansdeisntgh.eTshtriesnregsthulotsf .rssceep iLnDrLelreeacseepotofrLcDomLpclehxolteosttheeroelnadnodsodmiree1c2t(iFoinguorfet1h)e. TPhCeSaKbi9l-/ 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)


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Giuliana Mombelli, Samuela Castelnuovo, Chiara Pavanello. Potential of PCSK9 as a new target for the management of LDL cholesterol, Research Reports in Clinical Cardiology, 2015, pp. 73-86, DOI: 10.2147/RRCC.S52961