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Cui H.L.,Baker Heart and Diabetes Institute | Ditiatkovski M.,Baker Heart and Diabetes Institute | Kesani R.,Baker Heart and Diabetes Institute | Bobryshev Y.V.,University of New South Wales | And 5 more authors.
FASEB Journal | Year: 2014

Patients with HIV are at an increased risk of cardiovascular disease. In this study we investigated the effect of Nef, a secreted HIV protein responsible for the impairment of cholesterol efflux, on the development of atherosclerosis in two animal models. ApoE-7- mice fed a high-fat diet and C57BL/6 mice fed a high-fat, high-cholesterol diet were injected with recombinant Nef (40 ng/injection) or vehicle, and the effects of Nef on development of atherosclerosis, inflammation, and dyslipidemia were assessed. In apoE -/- mice, Nef significantly increased the size of atherosclerotic lesions and caused vessel remodeling. Nef caused elevation of total cholesterol and triglyceride levels in the plasma while reducing high-density lipoprotein cholesterol levels. These changes were accompanied by a reduction of ABCA1 abundance in the liver, but not in the vessels. In C57BL/6 mice, Nef caused a significant number of lipid-laden macrophages presented in ad-ventitia of the vessels; these cells were absent from the vessels of control mice. Nef caused sharp elevations of plasma triglyceride levels and body weight. Taken together, our findings suggest that Nef causes dyslipidemia and accumulation of cholesterol in macrophages within the vessel wall, supporting the role of Nef in pathogenesis of atherosclerosis in HIV-infected patients. © FASEB.

Xu Q.,Shanghai JiaoTong University | Meng S.,Shanghai JiaoTong University | Liu B.,Shanghai JiaoTong University | Li M.-Q.,Tongji University | And 3 more authors.
Clinical and Experimental Pharmacology and Physiology | Year: 2014

Summary: Dysfunction of endothelial progenitor cells (EPC) contribute to diabetic vascular disease. MicroRNAs (miRNAs) are key regulators of diverse cellular processes, including angiogenesis. We recently reported that downregulated miR-130a in patients with Type 2 diabetes mellitus (DM) results in EPC dysfunction, including increased apoptosis, likely via its target runt-related transcription factor 3 (Runx3). However, whether miR-130a affects the autophagy of EPC is unknown. The aim of the present study was to explore the effects of miR-130a on the autophagy and cell death of EPC, as well as their expression of Beclin 1 (BECN1; an initiator of autophagosome formation) and the anti-apoptotic protein Bcl2 (which binds to and inactivates BECN1), and the role of Runx3 in mediating these effects. The EPC were cultured from peripheral blood mononuclear cells of diabetic patients and non-diabetic controls. Cells were transfected with an miR-130a inhibitor, or mimic-miR-130a or mimic-miR-130a plus lentiviral vector expressing Runx3 to manipulate miR-130a and/or Runx3 levels. The number of autophagosomes was counted under transmission electron microscopy and cell death was examined by flow cytometry. The mRNA expression of Beclin1 was measured by real-time polymerase chain reaction and the protein expression of Beclin1 and Bcl2 was determined by western blotting. Both the number of autophagosomes and Beclin1 expression were increased in EPC from patients with DM. Inhibition of miR-130a increased the number of autophagosomes and Beclin1 expression, but attenuated Bcl2 expression. Overexpression of miR-130a decreased the number of autophagosomes, cell death and Beclin1 expression, but promoted Bcl2 expression; these effects were mediated by Runx3. In conclusion, miR-130a is important for maintaining normal autophagy levels and promoting the survival of EPC via regulation of Bcl-2 and Beclin1 expression, via Runx3. MiR-130a may be a regulator linking apoptosis and the autophagy of EPC. © 2014 Wiley Publishing Asia Pty Ltd.

Ditiatkovski M.,Baker Heart and Diabetes Institute | D'Souza W.,Baker Heart and Diabetes Institute | Kesani R.,Baker Heart and Diabetes Institute | Chin-Dusting J.,Baker Heart and Diabetes Institute | And 3 more authors.
PLoS ONE | Year: 2013

Apolipoprotein A-I (apoA-I) mimetic peptides are considered a promising novel therapeutic approach to prevent and/or treat atherosclerosis. An apoA-I mimetic peptide ELK-2A2K2E was designed with a reductionist approach and has shown exceptional activity in supporting cholesterol efflux but modest anti-inflammatory and anti-oxidant properties in vitro. In this study we compared these in vitro properties with the capacity of this peptide to modify rates of reverse cholesterol transport and development of atherosclerosis in mouse models. The peptide enhanced the rate of reverse cholesterol transport in C57BL/6 mice and reduced atherosclerosis in Apoe-/- mice receiving a high fat diet. The peptide modestly reduced the size of the plaques in aortic arch, but was highly active in reducing vascular inflammation and oxidation. Administration of the peptide to Apoe-/- mice on a high fat diet reduced the levels of total, high density lipoprotein and non-high density lipoprotein cholesterol and triglycerides. It increased the proportion of smaller HDL particles in plasma at the expense of larger HDL particles, and increased the capacity of the plasma to support cholesterol efflux. Thus, ELK-2A2K2E peptide reduced atherosclerosis in Apoe-/- mice, however, the functional activity profile after chronic in vivo administration was different from that found in acute in vitro studies.

D'Souza W.,Baker Heart and Diabetes Institute | Stonik J.A.,U.S. National Institutes of Health | Murphy A.,Baker Heart and Diabetes Institute | Demosky S.J.,U.S. National Institutes of Health | And 5 more authors.
Circulation Research | Year: 2010

Rationale: Apolipoprotein (apoA)-I mimetic peptides are a promising type of antiatherosclerosis therapy, but how the structural features of these peptides relate to the multiple antiatherogenic functions of HDL is poorly understood. Objective: To establish structure/function relationships of apoA-I mimetic peptides with their antiatherogenic functions. Methods and results: Twenty-two bihelical apoA-I mimetic peptides were investigated in vitro for the capacity and specificity of cholesterol efflux, inhibition of inflammatory response of monocytes and endothelial cells, and inhibition of low-density lipoprotein (LDL) oxidation. It was found that mean hydrophobicity, charge, size of hydrophobic face, and angle of the link between the helices are the major factors determining the efficiency and specificity of cholesterol efflux. The peptide with optimal parameters was more effective and specific toward cholesterol efflux than human apoA-I. Charge and size of hydrophobic face were also the major factors affecting antiinflammatory properties, and the presence of cysteine and histidine residues was the main factor determining antioxidant properties. There was no significant correlation between capacities of the peptides to support individual functions; each function had its own optimal set of features. Conclusions: None of the peptides was equally effective in all the antiatherogenic functions tested, suggesting that different functions of HDL may have different mechanisms and different structural requirements. The results do suggest, however, that rationalizing the design of apoA-I mimetic peptides may improve their therapeutic value and may lead to a better understanding of mechanisms of various antiatherogenic functions of HDL. © 2010 American Heart Association, Inc.

Osei-Hwedieh D.O.,U.S. National Institutes of Health | Amar M.,U.S. National Institutes of Health | Sviridov D.,Baker Heart and Diabetes Institute | Remaley A.T.,U.S. National Institutes of Health
Pharmacology and Therapeutics | Year: 2011

Apolipoprotein mimetic peptides are short synthetic peptides that share structural, as well as biological features of native apolipoproteins. The early positive clinical trials of intravenous preparations of apoA-I, the main protein component of high density lipoproteins (HDL), have stimulated great interest in the use of apolipoprotein mimetic peptides as possible therapeutic agents. Currently, there are a wide variety of apolipoprotein mimetic peptides at various stages of drug development. These peptides typically have been designed to either promote cholesterol efflux or act as anti-oxidants, but they usually exert other biological effects, such as anti-inflammatory and anti-thrombotic effects. Uncertainty about which of these biological properties is the most important for explaining their anti-atherogenic effect is a major unresolved question in the field. Structure-function studies relating the in vitro properties of these peptides to their ability to reduce atherosclerosis in animal models may uncover the best rationale for the design of these peptides and may lead to a better understanding of the mechanisms behind the atheroprotective effect of HDL. Copyright © 2011 Published by Elsevier Inc. All rights reserved.

Hoang A.,Baker Heart and Diabetes Institute | Drew B.G.,Baker Heart and Diabetes Institute | Low H.,Baker Heart and Diabetes Institute | Remaley A.T.,U.S. National Institutes of Health | And 3 more authors.
European Heart Journal | Year: 2012

Objectives Infusion of reconstituted HDL (rHDL) leads to changes in HDL metabolism as well as to an increased capacity of plasma to support cholesterol efflux providing an opportunity to investigate mechanisms linking cholesterol efflux to changes in plasma HDL. Methods and results Patient plasmas after infusion of rHDL were tested ex vivo for their capacity to stimulate cholesterol efflux. Reconstituted HDL enhanced mobilization of cholesterol from tissues in vivo as shown by rising HDL cholesterol concentrations over the infusion period. Infusion of rHDL in vivo led to increased cholesterol efflux ex vivo; surprisingly, removing apoB-containing lipoproteins while preserving all HDL subfractions eliminated this increase. Infusion of rHDL led to the remodelling of plasma HDL; however, the capacity of plasma to support cholesterol efflux did not correlate with changes in the concentrations of any of HDL subfractions. Unmodified rHDL accounted for only a proportion of the increment in cholesterol efflux capacity. Furthermore, studies using HeLa and BHK cells overexpressing ABCA1, ABCG1, and SR-B1 showed that the contribution of these cellular mediators of cholesterol efflux to the enhanced capacity of plasma for the efflux was minimal. Conclusion Enhanced cholesterol efflux from tissues requires the presence of apoB-containing lipoproteins and may involve enhanced flow of cholesterol through multiple components of the reverse cholesterol transport pathway rather than being determined by a specific HDL subfraction. © 2011 The Author.

1. Plasma levels of high-density lipoprotein (HDL) are believed to be inversely related to coronary artery disease. High-density lipoprotein plays a key role in the process of reverse cholesterol transport, by which HDL is able to extract excess cholesterol from peripheral tissues and transfer it to the liver for biliary excretion. 2. Efflux of lipids (cholesterol and phospholipids) is the first step in reverse cholesterol transport. Several cellular membrane transporters, including ABCA1 and ABCG1, as well as scavenger receptor (SR)-BI receptor, are believed to facilitate the active efflux of cholesterol to lipid-poor apolipoprotein A-I and mature HDL, respectively. Furthermore, overexpression or deletion of one or more specific genes supports the view that HDL is involved in cholesterol efflux. 3. In conclusion, current evidence supports a critical role for HDL in atheroprotection via an active efflux pathway through reverse cholesterol transport, with the substantial support of appropriate functions of cell donors. © 2010 Blackwell Publishing Asia Pty Ltd.

Nestel P.,Baker Heart and Diabetes Institute
Clinical Therapeutics | Year: 2014

Objective The goal of this article was to review the causal link between trans fatty acids (TFA) produced from partially hydrogenated vegetable oil (PHVO) and cardiovascular disease (CVD) risk and its likely mechanisms. The potential risk of TFA from ruminant dairy and meats, which are currently the major sources of dietary TFA, is also discussed. Methods Evidence was derived from observational studies of large cohorts followed up prospectively; from randomized controlled trials of clinical interventions; and from specific case-control studies that investigated biomarkers in tissues. Searches included PubMed and Medline from 1990 to 2013. Results Despite TFA from PHVO being associated more strongly with CVD risk than even saturated fats, it may prove difficult to totally eliminate PHVO from all foods. This raises the issue of the lower limit of TFA consumption below which CVD risk is not increased. Limits of <1% of total energy have been suggested. The major mechanism underlying the increased CVD risk from TFA is an increase in LDL-C and Lp(a) lipoproteins and a decrease in HDL-C; increased inflammation and adverse effects on vascular function have also been shown. Both PHVO and ruminant TFA comprise a range of isomers, some specific to each source but including a substantial commonality that supports findings of similar adverse effects at equivalent intakes of TFA. However, the amount of TFA in ruminant fat is relatively small; this limits the CVD risk from eating ruminant products, an inference supported by analysis of prospective cohort studies. Conclusions Two key challenges to the health industry arise from this evidence. They must first determine whether a small intake of TFA from PHVO is safe and what constitutes a safe amount. They must also determine whether TFA from ruminant fat in currently consumed amounts represent limited cardiovascular risk that is balanced by the nutritional benefits of dairy products. © 2014 Elsevier HS Journals, Inc.

Carew R.M.,Baker Heart and Diabetes Institute | Wang B.,Baker Heart and Diabetes Institute | Kantharidis P.,Baker Heart and Diabetes Institute
Cell and Tissue Research | Year: 2012

It is clear that the well-described phenomenon of epithelial - mesenchymal transition (EMT) plays a pivotal role in embryonic development, wound healing, tissue regeneration, organ fibrosis and cancer progression. EMTs have been classified into three subtypes based on the functional consequences and biomarker context in which they are encountered. This review will highlight findings on type II EMT as a direct contributor to the kidney myofibroblast population in the development of renal fibrosis, specifically in diabetic nephropathy, the signalling molecules and the pathways involved in type II EMT and changes in the expression of specific miRNA with the EMT process. These findings have provided new insights into the activation and development of EMT during disease processes and may lead to possible therapeutic interventions to suppress EMTs and potentially reverse organ fibrosis. © Springer-Verlag 2011.

Nestel P.,Baker Heart and Diabetes Institute | Hoang A.,Baker Heart and Diabetes Institute | Sviridov D.,Baker Heart and Diabetes Institute | Straznicky N.,Baker Heart and Diabetes Institute
International Journal of Obesity | Year: 2012

Objective: In vitro measurements of cholesterol efflux from macrophages have recently been shown to associate with cardiovascular risk. We investigated whether cholesterol efflux from macrophages incubated with plasmas from overweight/obese subjects with metabolic syndrome was influenced by the presence of insulin resistance.Methods:Plasmas were obtained from 47 men and women with metabolic syndrome, of whom 25 were found to be insulin resistant (IR) and 22 insulin sensitive (IS) (Matsuda, De Fronzo equation based on oral glucose tolerance test). Activated human macrophage THP-1 cells in which cholesterol had been radiolabelled were incubated with the subjects plasmas to allow calculation of % cholesterol efflux.Results:Body mass index and waist measurements, as well as plasma lipid levels, did not differ between the two groups. Homeostatic model assessment-insulin resistance value as well as plasma insulin and leptin concentrations were higher in IR subjects. Cholesterol efflux was found to be significantly greater with plasmas from IR subjects (9.1%) than from IS subjects (6.7%) (P=0.005). Further, cholesterol efflux was significantly inversely associated with insulin sensitivity index (P<0.001), directly with arterial insulin concentration (P<0.001) and directly with cholesteryl ester transfer protein (CETP) mass (P=0.044).Conclusion:Plasmas from overweight subjects with insulin resistance induced greater in vitro cholesterol efflux compared with IS subjects. Efflux inversely correlated with insulin sensitivity suggesting an increase in reverse cholesterol transport in the IR state that may lead to greater transfer of cholesterol to apoB lipoproteins from high-density lipoproteins via CETP as a factor in the association between IR and atherosclerosis. © 2012 Macmillan Publishers Limited All rights reserved.

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