Fatiha Tabet

University of New South Wales, Kensington, New South Wales, Australia

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Publications (35)187.25 Total impact

  • Philip J. Barter · Fatiha Tabet · Kerry A Rye

    No preview · Article · Sep 2015 · The Journal of Lipid Research
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    ABSTRACT: Objective: Lymphatic endothelial dysfunction underlies the pathogenesis of many chronic inflammatory disorders. The proinflammatory cytokine tumor necrosis factor (TNF) is known for its role in disrupting the function of the lymphatic vasculature. This study investigates the ability of apo AI, the principal apolipoprotein of high-density lipoproteins, to preserve the normal function of lymphatic endothelial cells treated with TNF. Approach and results: TNF decreased the ability of lymphatic endothelial cells to form tube-like structures. Preincubation of lymphatic endothelial cells with apo AI attenuated the TNF-mediated inhibition of tube formation in a concentration-dependent manner. In addition, apo AI reversed the TNF-mediated suppression of lymphatic endothelial cell migration and lymphatic outgrowth in thoracic duct rings. Apo AI also abrogated the negative effect of TNF on lymphatic neovascularization in an ATP-binding cassette transporter A1-dependent manner. At the molecular level, this involved downregulation of TNF receptor-1 and the conservation of prospero-related homeobox gene-1 expression, a master regulator of lymphangiogenesis. Apo AI also re-established the normal phenotype of the lymphatic network in the diaphragms of human TNF transgenic mice. Conclusions: Apo AI restores the neovascularization capacity of the lymphatic system during TNF-mediated inflammation. This study provides a proof-of-concept that high-density lipoprotein-based therapeutic strategies may attenuate chronic inflammation via its action on lymphatic vasculature.
    Full-text · Article · Sep 2015 · Arteriosclerosis Thrombosis and Vascular Biology
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    ABSTRACT: MicroRNAs (miRNAs) regulate a wide variety of biological processes and contribute to metabolic homeostasis. Here, we demonstrate that microRNA-223 (miR-223), an miRNA previously associated with inflammation, also controls multiple mechanisms associated with cholesterol metabolism. miR-223 promoter activity and mature levels were found to be linked to cellular cholesterol states in hepatoma cells. Moreover, hypercholesterolemia was associated with increased hepatic miR-223 levels in athero-prone mice. miR-223 was found to regulate high-density lipoprotein-cholesterol (HDL-C) uptake, through direct targeting and repression of scavenger receptor BI, and to inhibit cholesterol biosynthesis through the direct repression of sterol enzymes 3-hydroxy-3-methylglutaryl-CoA synthase 1 and methylsterol monooxygenase 1 in humans. Additionally, miR-223 was found to indirectly promote ATP-binding cassette transporter A1 expression (mRNA and protein) through Sp3, thereby enhancing cellular cholesterol efflux. Finally, genetic ablation of miR-223 in mice resulted in increased HDL-C levels and particle size, as well as increased hepatic and plasma total cholesterol levels. In summary, we identified a critical role for miR-223 in systemic cholesterol regulation by coordinated posttranscriptional control of multiple genes in lipoprotein and cholesterol metabolism.
    Full-text · Article · Sep 2014 · Proceedings of the National Academy of Sciences

  • No preview · Article · Aug 2014 · Atherosclerosis

  • No preview · Article · Aug 2014 · Atherosclerosis
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    ABSTRACT: Objectives Do elevated PCSK9 levels constitute an even greater risk for people who already have reduced LDL receptor (LDLR) levels, such as heterozygous familial hypercholesterolemic (HeFH) patients? Background As a circulating inhibitor of the LDLR, PCSK9 is an attractive target to lower LDL-cholesterol (LDL-C). Methods Circulating PCSK9 was measured by ELISA in non-treated HeFH patients carrying either a D206E (n=237), V408M (n=117), or D154N (n=38) LDLR missense mutation and in normolipidemic controls (n=152). Skin fibroblasts and lymphocytes were isolated from a subset of patients and grown in 0·5% serum and mevastatin with increasing amounts of recombinant PCSK9. LDLR abundance at the cell surface was determined by flow cytometry. Results PCSK9 dose-dependently reduced LDLR expression in control and FH fibroblasts to similar extents, by up to 77±8% and 82±7%. Likewise, PCSK9 reduced LDLR abundance by 39±8% in non-FH and by 45±10% in HeFH lymphocytes, irrespective of their LDLR mutation status. We found positive correlations of the same magnitude between PCSK9 and LDL-C in controls (β=0·22, p=0·0003), D206E ( β=0·20, p=0·0002), V408M ( β=0·24, p=0·0002), and D154N ( β=0·25, p=0·048) HeFH patients. The strengths of these associations were all similar. Conclusion Elevated PCSK9 levels are equally detrimental for HeFH and non-FH patients: a 100ng/mL increase in PCSK9 will lead to an increase in LDL-C of 0·20-0·25mmol/L in controls and HeFH alike, irrespective of their LDLR mutation. This explains why non-FH and HeFH patients respond equally well to monoclonal antibodies targeting PCSK9.
    Full-text · Article · Jun 2014 · Journal of the American College of Cardiology

  • No preview · Conference Paper · Jun 2014
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    ABSTRACT: High-density lipoproteins (HDL) have many biological functions, including reducing endothelial activation and adhesion molecule expression. We recently reported that HDL transport and deliver functional microRNAs (miRNA). Here we show that HDL suppresses expression of intercellular adhesion molecule 1 (ICAM-1) through the transfer of miR-223 to endothelial cells. After incubation of endothelial cells with HDL, mature miR-223 levels are significantly increased in endothelial cells and decreased on HDL. However, miR-223 is not transcribed in endothelial cells and is not increased in cells treated with HDL from miR-223(-/-) mice. HDL inhibit ICAM-1 protein levels, but not in cells pretreated with miR-223 inhibitors. ICAM-1 is a direct target of HDL-transferred miR-223 and this is the first example of an extracellular miRNA regulating gene expression in cells where it is not transcribed. Collectively, we demonstrate that HDL's anti-inflammatory properties are conferred, in part, through HDL-miR-223 delivery and translational repression of ICAM-1 in endothelial cells.
    No preview · Article · Feb 2014 · Nature Communications
  • Kasey C Vickers · Kerry-Anne Rye · Fatiha Tabet
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    ABSTRACT: Physiological and pathological roles for small non-encoding miRNAs (microRNAs) in the cardiovascular system have recently emerged and are now widely studied. The discovery of widespread functions of miRNAs has increased the complexity of gene-regulatory processes and networks in both the cardiovascular system and cardiovascular diseases. Indeed, it has recently been shown that miRNAs are implicated in the regulation of many of the steps leading to the development of cardiovascular disease. These findings represent novel aspects in miRNA biology and, therefore, our understanding of the role of these miRNAs during the pathogenesis of cardiovascular disease is critical for the development of novel therapies and diagnostic interventions. The present review will focus on understanding how miRNAs are involved in the onset and development of cardiovascular diseases.
    No preview · Article · Feb 2014 · Clinical Science

  • No preview · Article · Jan 2014 · Arteriosclerosis Thrombosis and Vascular Biology
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    ABSTRACT: This study shows whether high-density lipoproteins (HDLs) and apolipoprotein A-I inhibit joint inflammation in streptococcal cell wall peptidoglycan-polysaccharide (PG-PS)-induced arthritis in female Lewis rats. Administration of PG-PS to female Lewis rats caused acute joint inflammation after 4 days, followed by remission by day 8. The animals subsequently developed chronic joint inflammation that persisted until euthanized at day 21. Treatment with apolipoprotein A-I 24 hours before and after PG-PS administration reduced the acute and chronic joint inflammation. Treatment with apolipoprotein A-I at days 7, 9, and 11 after PG-PS administration reduced the chronic joint inflammation. Treatment with apolipoprotein A-I or reconstituted HDLs consisting of apolipoprotein A-I complexed with phosphatidylcholine 24 hours before and at days 1, 7, 9, and 11 after PG-PS administration reduced acute and chronic joint inflammation. Treatment with apolipoprotein A-I also reduced the inflammatory white blood cell count, synovial fluid proinflammatory cytokine levels, synovial tissue macrophage accumulation, as well as toll-like receptor 2, and inflammatory cytokine expression. At the molecular level, preincubation of human monocyte-derived macrophages with apolipoprotein A-I or reconstituted HDLs before PG-PS stimulation inhibited the PG-PS-induced increase in toll-like receptor 2 and myeloid differentiation primary response gene (88) mRNA levels, nuclear factor-κB activation, and proinflammatory cytokine production. The effects of apolipoprotein A-I and reconstituted HDLs were abolished by transfecting the human monocyte-derived macrophages with ATP-binding cassette transporter A1 or G1 siRNA. Apolipoprotein A-I and reconstituted HDLs attenuate PG-PS-induced arthritis in the rat. Studies in human monocyte-derived macrophages indicate that this benefit may be because of the inhibition of toll-like receptor 2 expression and decreased nuclear factor-κB activation in macrophages.
    Preview · Article · Dec 2013 · Arteriosclerosis Thrombosis and Vascular Biology
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    ABSTRACT: The purpose of this study was to investigate whether high levels of circulating proprotein convertase subtilisin kexin type 9 (PCSK9) would increase cardiovascular risk in statin-treated patients. Statins activate low-density lipoprotein (LDL) receptor gene expression, thus lowering plasma LDL levels. But statins also activate the expression of PCSK9, a secreted inhibitor of the LDL receptor, thereby limiting their beneficial effects. We have measured the plasma PCSK9 levels of 1,613 patients with stable coronary heart disease enrolled in the Treating to New Targets study, a randomized trial that compared the efficacy of high- versus low-dose atorvastatin. After a run-in period with atorvastatin 10 mg daily, patients were randomized to either continue with 10 mg or be up-titrated to 80 mg of atorvastatin, and followed during 5 years for major cardiovascular events (MCVEs). Circulating PCSK9 levels measured at randomization were predictive of clinical outcomes in the group randomized to remain on atorvastatin 10 mg (p = 0.039), but not in the group that intensified atorvastatin treatment to 80 mg (p = 0.24). Further, PCSK9 levels measured 1 year post-randomization did not change upon increase of the statin dose. PCSK9 levels predict cardiovascular events in patients treated with low-dose atorvastatin. (A Study to Determine the Degree of Additional Reduction in CV Risk in Lowering LDL Below Minimum Target Levels [TNT]; NCT00327691).
    Full-text · Article · May 2012 · Journal of the American College of Cardiology

  • No preview · Conference Paper · Jan 2012
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    ABSTRACT: The functional significance and regulation of NAD(P)H oxidase (Nox) isoforms by angiotensin II (Ang II) and endothelin-1 (ET-1) in vascular smooth muscle cells (VSMCs) from normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) was studied. Expression of Nox1, Nox2, and Nox4 (gene and protein) and NAD(P)H oxidase activity were increased in SHR. Basal NAD(P)H oxidase activity was blocked by GKT136901 (Nox1/4 inhibitor) and by Nox1 siRNA in WKY cells and by siNOX1 and siNOX2 in SHR. Whereas Ang II increased expression of all Noxes in WKY, only Nox1 was influenced in SHR. Ang II-induced NAD(P)H activity was inhibited by siNOX1 in WKY and by siNOX1 and siNOX2 in SHR. ET-1 upregulated Nox expression only in WKY and increased NAD(P)H oxidase activity, an effect inhibited by siNOX1 and siNOX2. Nox1 co-localized with Nox2 but not with Nox4, implicating association between Nox1 and Nox2 but not between Nox1 and Nox4. These data highlight the complexity of Nox biology in VSMCs, emphasising that more than one Nox member, alone or in association, may be involved in NAD(P)H oxidase-mediated •O(2)(-) production. Nox1 regulation by Ang II, but not by ET-1, may be important in •O(2)(-) formation in VSMCs from SHR.
    Full-text · Article · Mar 2011 · Journal of the American Society of Hypertension
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    ABSTRACT: The goal of this study was to investigate the mechanisms by which apolipoprotein (apo) A-I, in the lipid-free form or as a constituent of discoidal reconstituted high-density lipoproteins ([A-I]rHDL), inhibits high-glucose-induced redox signaling in human monocyte-derived macrophages (HMDM). HMDM were incubated under normal (5.8 mmol/L) or high-glucose (25 mmol/L) conditions with native high-density lipoproteins (HDL) lipid-free apoA-I from normal subjects and from subjects with type 2 diabetes (T2D) or (A-I)rHDL. Superoxide (O2-) production was measured using dihydroethidium fluorescence. NADPH oxidase activity was assessed using lucigenin-derived chemiluminescence and a cyotochrome c assay. p47phox translocation to the plasma membrane, Nox2, superoxide dismutase 1 (SOD1), and SOD2 mRNA and protein levels were determined by real-time polymerase chain reaction and Western blotting. Native HDL induced a time-dependent inhibition of O2- generation in HMDM incubated with 25 mmol/L glucose. Lipid-free apoA-I and (A-I)rHDL increased SOD1 and SOD2 levels and attenuated 25 mmol/L glucose-mediated increases in cellular O2-, NADPH oxidase activity, p47 translocation, and Nox2 expression. Lipid-free apoA-I mediated its effects on Nox2, SOD1, and SOD2 via ABCA1. (A-I)rHDL-mediated effects were via ABCG1 and scavenger receptor BI. Lipid-free apoA-I from subjects with T2D inhibited reactive oxygen species generation less efficiently than normal apoA-I. Native HDL, lipid-free apoA-I and (A-I)rHDL inhibit high-glucose-induced redox signaling in HMDM. The antioxidant properties of apoA-I are attenuated in T2D.
    Preview · Article · Feb 2011 · Arteriosclerosis Thrombosis and Vascular Biology
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    ABSTRACT: Type 2 diabetes is characterized by impaired beta-cell secretory function, insulin resistance, reduced high-density lipoprotein (HDL) levels, and increased cardiovascular risk. Given the current interest in therapeutic interventions that raise HDLs levels, this study investigates the effects of HDLs on insulin secretion from beta-cells. Incubation of Min6 cells and primary islets under basal or high-glucose conditions with either apolipoprotein (apo) A-I or apoA-II in the lipid-free form, as a constituent of discoidal reconstituted HDLs (rHDLs), or with HDLs isolated from human plasma increased insulin secretion up to 5-fold in a calcium-dependent manner. The increase was time and concentration dependent. It was also K(ATP) channel and glucose metabolism dependent under high-glucose, but not low-glucose, conditions. The lipid-free apolipoprotein-mediated increase in insulin secretion was ATP binding cassette (ABC) transporter A1 and scavenger receptor-B1 dependent. The rHDL-mediated increase in insulin secretion was ABCG1 dependent. Exposure of beta-cells to lipid-free apolipoproteins also increased insulin mRNA expression and insulin secretion without significantly depleting intracellular insulin or cholesterol levels. These results establish that lipid-free and lipid-associated apoA-I and apoA-II increase beta-cell insulin secretion and indicate that interventions that raise HDLs levels may be beneficial in type 2 diabetes.
    No preview · Article · May 2010 · Arteriosclerosis Thrombosis and Vascular Biology
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    ABSTRACT: The goal of this study was to investigate the effects of nonenzymatic glycation on the antiinflammatory properties of apolipoprotein (apo) A-I. Rabbits were infused with saline, lipid-free apoA-I from normal subjects (apoA-I(N)), lipid-free apoA-I nonenzymatically glycated by incubation with methylglyoxal (apoA-I(Glyc in vitro)), nonenzymatically glycated lipid-free apoA-I from subjects with diabetes (apoA-I(Glyc in vivo)), discoidal reconstituted high-density lipoproteins (rHDL) containing phosphatidylcholine and apoA-I(N), (A-I(N))rHDL, or apoA-I(Glyc in vitro), (A-I(Glyc in vitro))rHDL. At 24 hours postinfusion, acute vascular inflammation was induced by inserting a nonocclusive, periarterial carotid collar. The animals were euthanized 24 hours after the insertion of the collar. The collars caused intima/media neutrophil infiltration and increased endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). ApoA-I(N) infusion decreased neutrophil infiltration and VCAM-1 and ICAM-1 expression by 89%, 90%, and 66%, respectively. The apoA-I(Glyc in vitro) infusion decreased neutrophil infiltration by 53% but did not reduce VCAM-1 or ICAM-1 expression. ApoA-I(Glyc in vivo) did not inhibit neutrophil infiltration or adhesion molecule expression. (A-I(Glyc in vitro))rHDL also inhibited vascular inflammation less effectively than (A-I(N))rHDL. The reduced antiinflammatory properties of nonenzymatically glycated apoA-I were attributed to a reduced ability to inhibit nuclear factor-kappaB activation and reactive oxygen species formation. Nonenzymatic glycation impairs the antiinflammatory properties of apoA-I.
    Full-text · Article · Apr 2010 · Arteriosclerosis Thrombosis and Vascular Biology

  • No preview · Article · Dec 2009 · Heart, Lung and Circulation

  • No preview · Article · Dec 2009 · Heart, Lung and Circulation
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    ABSTRACT: OBJECTIVE: The apolipoprotein (apo)A-I mimetic peptide 5A is highly specific for ATP-binding cassette transporter (ABC)A1-mediated cholesterol efflux. We investigated whether the 5A peptide shares other beneficial features of apoA-I, such as protection against inflammation and oxidation. Methods- New Zealand white rabbits received an infusion of apoA-I, reconstituted high-density lipoprotein (HDL) containing apoA-I ([A-I]rHDL), or the 5A peptide complexed with phospholipids (1-palmitoyl-2-linoleoyl phosphatidylcholine [PLPC]), before inserting a collar around the carotid artery. Human coronary artery endothelial cells (HCAECs) were incubated with (A-I)rHDL or 5A/PLPC before stimulation with tumor necrosis factor alpha. Results- ApoA-I, (A-I)rHDL, and 5A/PLPC reduced the collar-mediated increase in (1) endothelial expression of cell adhesion molecules vascular cell adhesion molecule-1 and intercellular adhesion molecule-1; (2) production, as well as the expression of the Nox4 catalytic subunits of the NADPH oxidase; and (3) infiltration of circulating neutrophils into the carotid intima-media. In HCAECs, both 5A/PLPC and (A-I)rHDL inhibited tumor necrosis factor-alpha-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression, as well as the nuclear factor kappaB signaling cascade and production. The effects of the 5A/PLPC complex were no longer apparent in HCAECs knocked down for ABCA1. CONCLUSIONS: Like apoA-I, the 5A peptide inhibits acute inflammation and oxidative stress in rabbit carotids and HCAECs. In vitro, the 5A peptide exerts these beneficial effects through interaction with ABCA1.
    Full-text · Article · Dec 2009 · Arteriosclerosis Thrombosis and Vascular Biology

Publication Stats

2k Citations
187.25 Total Impact Points


  • 2014-2015
    • University of New South Wales
      • • School of Medical Sciences
      • • Centre for Vascular Research (CVR)
      Kensington, New South Wales, Australia
  • 2009-2014
    • Heart Research Institute
      • Free Radical Group
      Newtown, New South Wales, Australia
  • 2013
    • University of Sydney
      Sydney, New South Wales, Australia
  • 2008-2011
    • University of Ottawa
      • Department of Medicine
      Ottawa, Ontario, Canada
  • 2003-2005
    • Université de Montréal
      • Department of Pharmacology
      Montréal, Quebec, Canada