PCSK9 and atherosclerosis: Beyond LDL-cholesterol lowering
Résumé
Pro-protein convertase subtilisin/kexin type 9 (PCSK9) is a critical regulator of LDL cholesterol (LDL-C) metabolism [1]. While Pcsk9 gain-of-function mutations are associated with autosomal dominant hypercholesterolemia and premature atherosclerosis [2], Pcsk9 loss-of-function mutations conversely lead to low levels of LDL-C and protection from coronary heart disease (CHD) [3]. Recent studies show that inhibition of PCSK9 with fully human monoclonal antibodies (mAb) to PCSK9 leads to a z60% LDL-C reduction in patients already treated with maximally tolerated statin therapy [4], validating PCSK9 as a very promising target for dyslipidemia and for secondary prevention of cardiovascular events. The current paradigm for PCSK9 biology is directly related to its role on the hepatic LDL receptor (LDLR) pathway. Briefly, after intra-cellular autocleavage, PCSK9 is secreted by the liver in the circulation , where it binds to the extracellular domain of the LDLR at the cell surface of the hepatocytes and targets it to lysosomes for degradation. Although the vast majority of studies have focused on the role of PCSK9 in the liver, an increasing body of evidence suggests that PCSK9 can also exert some extra-hepatic actions (for review [5]). Beside the liver, PCSK9 is also expressed at high levels in many tissues, such as the intestine, the kidney, the lung, the pancreas and the brain. The function of PCSK9 in these extra-hepatic organs remains largely unclear. Ferri et al. [6] in 2012 showed that PCSK9 is expressed at a significant level in vascular smooth muscle cells (VSMCs), as well as in human atherosclerotic plaques. In the same study, co-culture experiments suggested that PCSK9 released by VSMCs is able to downregulate LDLR expression in macrophages [6]. In 2015, Ding et al. [7] published that VSMCs release significant amounts of PCSK9 (more than endothelial cells) with maximal release at low shear stress (3e6 dyn/cm 2), and showed a greater PCSK9 expression in aortic branch-points and aorta-iliac bifurcation regions of the mouse aorta that express low shear stress. These regions are more prone to atherosclerosis that other regions. In this issue of Atherosclerosis, Ferri et al. give further insights into the role of PCSK9 in VSMC biology and atherogenesis [8]. Indeed, they showed that Pcsk9-deficient (Pcsk9 À/À) mice display reduced neointimal formation, a critical step in atherogenesis, following perivascular injury induced by placement of a non-occlusive collar along the ca-rotid artery [8]. The carotid lesions in Pcsk9 À/À mice had a lower content of SMCs and collagen, without a difference in macrophages content [8]. Importantly, by using primary VSMCs from Pcsk9 À/À and Pcsk9 þ/þ mice, the authors demonstrated that PSCK9 regulates VSMC proliferation rate and migratory capacity [8]. This study reinforces previous work highlighting a role for PCSK9 in VSMC biology. Inflammation induces marked changes in lipid and lipoprotein metabolism, as well as in PCSK9 expression [9]. PCSK9 expression in VSMCs is also upregulated upon treatment of cells with lipopolysaccharide, a potent inflammatory stimulus. In this process, NADPH oxidase-related cellular reactive oxygen species (ROS) generation and the redox-sensitive transcription factors nuclear factor kappa (NF-kB) activation play an important role [9]. Recently, Ding et al. [10] have suggested the existence of a positive feedback interplay between VSMC-derived PCSK9 and mitochon-drial DNA damage in the pro-inflammatory milieu involving mito-chondrial ROS (mtROS) [10]. Interestingly, mtDNA damage and excess generation of mtROS are frequently observed in atheroscle-rotic tissues. LOX-1 is one of the major receptors for oxidized low-density lipoprotein (ox-LDL) uptake, which is activated in many in-flammatory disease states, including atherosclerosis. Deletion of LOX-1 reduces atherogenesis in LDLR À/À mice fed a high-cholesterol diet [11], in a large part by reducing inflammatory reaction and pro-oxidant state in the arterial wall [12]. A positive feedback between PCSK9 and LOX-1 in VSMCs has been identified, wherein PCSK9 stimulates LOX-1 expression at transcriptional levels, and LOX-1 activation stimulates PCSK9 expression [13]. mtROS seems to play a critical role in this cross-talk which is exacerbated in inflammatory states. It is possible that PCSK9 cooperates with LOX-1 in atherogenesis, particularly during inflammatory states. These concepts, summarized in Fig. 1, raise an interesting possibility that PCSK9 inhibitors might inhibit atherogenesis in hy-percholesterolemic states by disrupting LOX-1 expression. The study by Ferri et al. [8] reinforces the hypothesis for an extra-hepatic action of PCSK9. It should be reminded here that one of the major breakthroughs in the field was the generation and characterization of liver-specific Pcsk9 À/À mice [14]. This study demonstrated that the liver is responsible for only two thirds of the hypocholesterolemic phenotype of global Pcsk9 À/À mice, highlighting the hypothesis that other organs are involved in the regulation of lipoprotein metabolism by PCSK9. It is plausible that DOI of original article: http://dx.