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Melbourne, Australia

Nestel P.,Baker Heart and Diabetes Institute
Clinical Therapeutics

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. Source

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. Source

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

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. Source

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

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. Source

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.

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. Source

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