International Journal of Molecular Sciences Review PCSK9 Biology and Its Role in Atherothrombosis Cristina Barale, Elena Melchionda, Alessandro Morotti and Isabella Russo * Department of Clinical and Biological Sciences, Turin University, I-10043 Orbassano, TO, Italy;
[email protected] (C.B.);
[email protected] (E.M.);
[email protected] (A.M.) * Correspondence:
[email protected]; Tel./Fax: +39-011-9026622 Abstract: It is now about 20 years since the first case of a gain-of-function mutation involving the as- yet-unknown actor in cholesterol homeostasis, proprotein convertase subtilisin/kexin type 9 (PCSK9), was described. It was soon clear that this protein would have been of huge scientific and clinical value as a therapeutic strategy for dyslipidemia and atherosclerosis-associated cardiovascular disease (CVD) management. Indeed, PCSK9 is a serine protease belonging to the proprotein convertase family, mainly produced by the liver, and essential for metabolism of LDL particles by inhibiting LDL receptor (LDLR) recirculation to the cell surface with the consequent upregulation of LDLR- dependent LDL-C levels. Beyond its effects on LDL metabolism, several studies revealed the existence of additional roles of PCSK9 in different stages of atherosclerosis, also for its ability to target other members of the LDLR family. PCSK9 from plasma and vascular cells can contribute to the development of atherosclerotic plaque and thrombosis by promoting platelet activation, leukocyte recruitment and clot formation, also through mechanisms not related to systemic lipid changes. These results further supported the value for the potential cardiovascular benefits of therapies based on PCSK9 inhibition. Actually, the passive immunization with anti-PCSK9 antibodies, evolocumab and alirocumab, is shown to be effective in dramatically reducing the LDL-C levels and attenuating CVD.