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  • In this study we implicate SCFFBXO

    2021-04-08

    In this study, we implicate SCFFBXO3 E3 ligase as a critical modulator of inflammation in atherosclerosis and demonstrate the efficacy of a small molecule FBXO3 inhibitor in suppressing inflammatory responses important in atherosclerosis. Specifically, individuals carrying a hypofunctioning genetic variant of FBXO3 manifest less atherosclerosis. Also, FBXO3 protein levels are increased in atherosclerotic plaques from subjects with symptomatic rather than asymptomatic atherosclerosis. Further, depletion or chemical inhibition of FBXO3 protein abolishes inflammatory responses to OxLDL without altering OxLDL uptake in macrophages. Thus, these studies implicate FBXO3 as a unique, druggable target for anti-inflammatory therapy in atherosclerosis.
    Materials and methods
    Results
    Discussion The role of pro-inflammatory pathways linked to the ubiquitin-proteasome system in the pathogenesis of atherosclerosis is an emerging area of investigation. Indeed, studies demonstrate putative roles of proteasomal blockade, protective effects of ubiquitin E3 ligases, and identification of related susceptibility genes, in the pathobiology of atherosclerosis [28]. This study implicates, for the first time, the SCFFBXO3 E3 ligase as a unique molecular regulator of inflammation in atherosclerosis. Specifically, we observed that i) individuals carrying a hypofunctioning genetic variant of FBXO3 manifest less atherosclerosis, ii) FBXO3 protein is present in cells of monocytic lineage within atherosclerotic plaques and its levels are elevated in subjects with symptomatic disease, and iii) FBXO3 inhibition via genetic silencing or chemical inhibition reduces OxLDL induced pro-inflammatory signal events in macrophages. Although additional proof-of-concept studies will be needed, these data suggest that selective FBXO3 targeting might serve as a potentially attractive pharmacotherapeutic strategy in this cardiovascular disorder. Inflammation is critical in the pathobiology of atherosclerosis. The inflammatory mediators impacted by FBXO3 described herein i.e. NF-κB, IL-1β, and TNF-α, and IL-8 have purported causal roles in atherosclerosis. For example, NF-κB activation is increased in mononuclear cells in human plaques [29] and in peripheral blood mononuclear cells in patients with unstable Procainamide HCl [30], and NF-κB inhibition attenuates atherosclerosis in hyperlipidemic mice [31]. IL-1β is a classic pro-inflammatory cytokine that has been linked to atherosclerosis and has been extensively studied [32]. Antagonizing IL1-β with a monoclonal antibody reduces atherosclerotic events in humans [3]. IL-8 causes rolling monocytes to adhere to endothelial cells, is mitogenic and chemotactic for vascular smooth muscle cells, and is increased within unstable atherosclerotic plaques [33,34]. TNF-α is a potent stimulator of several of the matrix metalloproteinases and of plasminogen activator inhibitor-1 [35] and has been identified as a player in several of the complications of atherosclerosis. Inhibition of TNF-α reduces atherosclerosis in apolipoprotein E knockout mice [35,36]. Hence, NF-κB antagonism, and reduced production of IL1-β, TNF-α, and IL-8 by upstream molecular inputs within the ubiquitin apparatus such as FBXO3 depletion would be expected to impair the development of atherosclerosis. Our study is not the first to implicate genetic variants in the FBXO3 gene as modulators of atherosclerosis risk. A genome wide association study that included over 5000 African-American participants and examined 2.5 million SNPs identified two variants in FBXO3 (rs11825259 and rs12291756) as among the top 67 SNPs associated with atherosclerosis risk. Unlike the SNP that was genotyped in our cohort, little is known about how rs11825259 and rs12291756 may alter function of FBXO3 [37]. Nonetheless, these independent findings corroborate the potential role of FBXO3 in regulating atherosclerosis in humans. There are multiple E3 ligases that can impact the pathobiology of atherosclerosis [38,39]. For example, HECT domain E3 ligases HUWE1 and NEDD4–1 control stability of the ATP-binding cassette transporter ABCG1 and ABCG4, both critical for cholesterol homeostasis [40]. In addition, the E3 ubiquitin ligase IDOL triggers lysosomal degradation of the low-density lipoprotein receptor [41]. Also, the ubiquitin ligase von Hippel-Lindau controls stability of hypoxia-inducible factor (HIF)-1a that in turn transcriptionally controls vascular endothelial growth factor (VGEF), an important regulator of neovascularization of atherosclerotic lesions [42]. Further, the E3 ubiquitin ligase ITCH modulates lipid metabolism and atherosclerosis by ubiquitination of SIRT6 and SREBP2, while genetic variants in E3 ligase RNF213 that regulates non-canonical Wnt signaling pathway have been associated with intracranial atherosclerosis [43,44]. While these studies demonstrate how the ubiquitin proteasome system can regulate atherosclerosis, no ubiquitin based therapies for atherosclerosis have been demonstrated as yet, nor have any SCF F-box protein E3 ligases been implicated in atherosclerosis to our knowledge.