Abstract
The relevance of PCSK9 in atherosclerosis progression is demonstrated by the benefits observed in patients that have followed PCSK9-targeted therapies. The impact of these therapies is attributed to the plasma lipid-lowering effect induced when LDLR hepatic expression levels are recovered after the suppression of soluble PCSK9. Different studies show that PCSK9 is involved in other mechanisms that take place at different stages during atherosclerosis development. Indeed, PCSK9 regulates the expression of key receptors expressed in macrophages that contribute to lipid-loading, foam cell formation and atherosclerotic plaque formation. PCSK9 is also a regulator of vascular inflammation and its expression correlates with pro-inflammatory cytokines release, inflammatory cell recruitment and plaque destabilization. Furthermore, anti-PCSK9 approaches have demonstrated that by inhibiting PCSK9 activity, the progression of atherosclerotic disease is diminished. PCSK9 also modulates thrombosis by modifying platelets steady-state, leukocyte recruitment and clot formation. In this review we evaluate recent findings on PCSK9 functions in cardiovascular diseases beyond LDL-cholesterol plasma levels regulation.
Highlights
Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is a soluble protein synthesized as a zymogen that undergoes autocatalytic cleavage in the endoplasmic reticulum [1]
Since PCSK9 was first described as the inducer of some FH pathologies, a lot of interest has been placed in the achievement of an effective inhibitory treatment
PCSK9 inhibitors administered to patients revealed a key role of PCSK9 in atherosclerotic disease as its inhibition reduced plasma LDLcholesterol levels with improved clinical cardiovascular outcomes demonstrating a multifactorial and pathophysiological role for PCSK9 in atherosclerosis progression
Summary
Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is a soluble protein synthesized as a zymogen that undergoes autocatalytic cleavage in the endoplasmic reticulum [1]. FH is an inherited disease where patients have LDL plasma levels above 190 mg/dL, contributing to an elevated risk of atherosclerotic plaque formation and coronary adverse events. This review will discuss the role of PCSK9 in modulating the activity of different cell lineages involved in atherosclerosis progression including macrophages, vascular smooth muscle cells (VSMC), endothelial cells (EC), lymphocytes and platelets and its associated cardiovascular risk.
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