Dose-Related Effects of Repeated ETC-216 (Recombinant Apolipoprotein A-IMilano/1-Palmitoyl-2-Oleoyl Phosphatidylcholine Complexes) Administrations on Rabbit Lipid-Rich Soft Plaques

Parolini, Cinzia; Marchesi, Matteo; Lorenzon, Paolo; Castano, Mauro; Balconi, Elena; Miragoli, Luigi; Chaabane, Linda; Morisetti, Alberto; Lorusso, Vito; Martin, Bradley J.; Bisgaier, Charles L.; Krause, Brian R.; Newton, Roger S.; Sirtori, Cesare R.; Chiesa, Giulia

doi:10.1016/j.jacc.2007.12.010

Cited by 87 publications

(63 citation statements)

References 18 publications

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“…The atheroprotective effects of HDL are mainly attributed to its ability to promote cholesterol efflux from lipid-laden extrahepatic cells, inhibit LDL oxidation and adhesion molecule expression, and protect endothelial cells (4). So elevating HDL level was recognized as a promising strategy to suppress atherosclerosis progression (30,31). Cholesteryl ester transfer protein (CETP) inhibitors were considered to be promising and applicable for markedly raising HDL levels in animal models (32).…”

Section: Hdl From Ms Patients Induces Oxidative Stress and Chop-mediamentioning

confidence: 99%

Oxidized high density lipoprotein induces macrophage apoptosis via toll-like receptor 4-dependent CHOP pathway

Yao¹,

Tian²,

Zhao³

et al. 2017

Journal of Lipid Research

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This article is available online at http://www.jlr.org Atherosclerosis, one of the prime causes of heart attack and stroke, has been well known as a lipid-driven inflammatory disease characterized by macrophage accumulation in subendothelial space. Apoptosis of macrophage-derived foam cells, especially in advanced atherosclerotic lesions where phagocytic clearance of dead and dying cells is defective, results in acellular necrotic lesions that are prone to plaque rupture and thrombosis formation, leading to the majority of acute vascular events (1). Thus, deeper understanding of the mechanisms of macrophage apoptosis may pave the way for developing novel therapeutic strategies to effectively prevent atherosclerotic plaque rupture and subsequent clinical complications (2). Oxidized LDL (ox-LDL) has been recognized as a major inducer, promoting foam cell formation and apoptosis in macrophages (3). In contrast, HDL exerts antiatherogenic functions such as promoting reverse cholesterol transport, suppressing inflammation, inhibiting LDL oxidation, and increasing endothelial nitric oxide production (4). However, accumulating evidence suggests that HDL, like LDL, is also susceptible to oxidative modification. Oxidized HDL Abstract Oxidized HDL (ox-HDL), unlike native HDL that exerts antiatherogenic effects, plays a proatherogenic role. However, the underlying mechanisms are not completely understood. This study was designed to explore the inductive effect of ox-HDL on endoplasmic reticulum (ER) stress-CCAAT-enhancer-binding protein homologous protein (CHOP)-mediated macrophage apoptosis and its upstream mechanisms. Our results showed that ox-HDL could be ingested by macrophages, causing intracellular lipid accumulation. As with tunicamycin (an ER stress inducer), ox-HDL induced macrophage apoptosis with concomitant activation of ER stress pathway, including nuclear translocation of activating transcription factor 6, phosphorylation of protein kinase-like ER kinase and eukaryotic translation initiation factor 2, and upregulation of glucose-regulated protein 78 and CHOP, which were inhibited by 4-phenylbutyric acid (PBA, an ER stress inhibitor) and CHOP gene silencing. Additionally, diphenyleneiodonium (DPI, an oxidative stress inhibitor), probucol (a reactive oxygen species scavenger), and toll-like receptor 4 (TLR4) silencing reduced ox-HDL-induced macrophage apoptosis, oxidative stress, and CHOP upregulation. Moreover, HDL isolated from patients with metabolic syndrome induced macrophage apoptosis, oxidative stress, and CHOP upregulation, which were blocked by PBA and DPI. These data indicate that ox-HDL may activate ER stress-CHOP-induced apoptotic pathway in macrophages via enhanced oxidative stress and that this pathway may be mediated by TLR4.

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Section: Hdl From Ms Patients Induces Oxidative Stress and Chop-mediamentioning

confidence: 99%

Oxidized high density lipoprotein induces macrophage apoptosis via toll-like receptor 4-dependent CHOP pathway

Yao¹,

Tian²,

Zhao³

et al. 2017

Journal of Lipid Research

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“…Despite a lipid profile that is usually associated with a high risk of premature cardiovascular disease, apoA-I M carriers display no increase in cardiovascular disease or events (10,14,15). This has led to speculation that apoA-I M is a gainof-function mutation that has enhanced cardio-protective effects (16)(17)(18)(19)(20)(21)(22), while others believe that wild-type (WT) apoA-I and apoA-I M are functionally equivalent (23,24). A clinical trial of repeated intravenous infusions of apoA-I M -phospholipid complexes demonstrated regression of existing atheromas after five weekly treatments (25,26).…”

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confidence: 99%

Structural and functional consequences of the Milano mutation (R173C) in human apolipoprotein A-I

Alexander

Tanaka

Kono

et al. 2009

Journal of Lipid Research

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Carriers of the apolipoprotein A-I Milano (apoA-I M ) variant, R173C, have reduced levels of plasma HDL but no increase in cardiovascular disease. Despite intensive study, it is not clear whether the removal of the arginine or the introduction of the cysteine is responsible for this altered functionality. We investigated this question using two engineered variations of the apoA-I M mutation: R173S apoA-I, similar to apoA-I M but incapable of forming a disulfide bond, and R173K apoA-I, a conservative mutation. Characterization of the lipid-free proteins showed that the order of stability was wild type≈R173K.R173S.R173C. Compared with wildtype apoA-I, apoA-I M had a lower affinity for lipids, while R173S apoA-I displayed intermediate affinity. The in vivo effects of the apoA-I variants were measured by injecting apoA-I-expressing adeno-associated virus into apoA-I-null mice. Mice that expressed the R173S variant again showed an intermediate phenotype. Thus, both the loss of the arginine and its replacement by a cysteine contribute to the altered properties of apoA-I M . The arginine is potentially involved in an intrahelical salt bridge with E169 that is disrupted by the loss of the positively charged arginine and repelled by the cysteine, destabilizing the helix bundle domain in the apoA-I molecule and modifying its lipid binding

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“…Indeed, administration of the predecessor compound ETC-216 was shown to reduce atherosclerotic plaque size and volume in mice and rabbit models (16)(17)(18)(19)(20) and in patients with acute coronary syndromes ( 21 ). However, no studies have been reported describing the effects of repeated administration of this product candidate on lipid and lipoprotein levels, either in animals or in man.…”

Section: Methodsmentioning

confidence: 99%

Effect of repeated apoA-IMilano/POPC infusion on lipids, (apo)lipoproteins, and serum cholesterol efflux capacity in cynomolgus monkeys

Kempen¹,

Gomaraschi

Bellibas

et al. 2013

Journal of Lipid Research

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Dose-Related Effects of Repeated ETC-216 (Recombinant Apolipoprotein A-IMilano/1-Palmitoyl-2-Oleoyl Phosphatidylcholine Complexes) Administrations on Rabbit Lipid-Rich Soft Plaques

Abstract: These results confirm the efficacy of ETC-216 for atherosclerosis treatment and provide guidance for dose selection and frequency to obtain a significant reduction of plaque volume.

Cited by 87 publications

References 18 publications

Oxidized high density lipoprotein induces macrophage apoptosis via toll-like receptor 4-dependent CHOP pathway

Oxidized high density lipoprotein induces macrophage apoptosis via toll-like receptor 4-dependent CHOP pathway

Structural and functional consequences of the Milano mutation (R173C) in human apolipoprotein A-I

Effect of repeated apoA-IMilano/POPC infusion on lipids, (apo)lipoproteins, and serum cholesterol efflux capacity in cynomolgus monkeys

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