82 research outputs found
Mitochondrial function is involved in regulation of cholesterol efflux to apolipoprotein (apo)A-I from murine RAW 264.7 macrophages
<p>Abstract</p> <p>Background</p> <p>Mitochondrial DNA damage, increased production of reactive oxygen species and progressive respiratory chain dysfunction, together with increased deposition of cholesterol and cholesteryl esters, are hallmarks of atherosclerosis. This study investigated the role of mitochondrial function in regulation of macrophage cholesterol efflux to apolipoprotein A-I, by the addition of established pharmacological modulators of mitochondrial function.</p> <p>Methods</p> <p>Murine RAW 264.7 macrophages were treated with a range of concentrations of resveratrol, antimycin, dinitrophenol, nigericin and oligomycin, and changes in viability, cytotoxicity, membrane potential and ATP, compared with efflux of [<sup>3</sup>H]cholesterol to apolipoprotein (apo) A-I. The effect of oligomycin treatment on expression of genes implicated in macrophage cholesterol homeostasis were determined by quantitative polymerase chain reaction, and immunoblotting, relative to the housekeeping enzyme, <it>Gapdh</it>, and combined with studies of this molecule on cholesterol esterification, <it>de novo</it> lipid biosynthesis, and induction of apoptosis. Significant differences were determined using analysis of variance, and Dunnett’s or Bonferroni post <it>t</it>-tests, as appropriate.</p> <p>Results</p> <p>The positive control, resveratrol (24 h), significantly enhanced cholesterol efflux to apoA-I at concentrations ≥30 μM. By contrast, cholesterol efflux to apoA-I was significantly inhibited by nigericin (45%; <it>p</it><0.01) and oligomycin (55%; <it>p</it><0.01), under conditions (10 μM, 3 h) which did not induce cellular toxicity or deplete total cellular ATP content. Levels of ATP binding cassette transporter A1 (ABCA1) protein were repressed by oligomycin under optimal efflux conditions, despite paradoxical increases in <it>Abca1</it> mRNA. Oligomycin treatment did not affect cholesterol biosynthesis, but significantly inhibited cholesterol esterification following exposure to acetylated LDL, and induced apoptosis at ≥30 μM. Finally, oligomycin induced the expression of genes implicated in both cholesterol efflux (<it>Abca1</it>, <it>Abcg4</it>, <it>Stard1</it>) and cholesterol biosynthesis (<it>Hmgr</it>, <it>Mvk</it>, <it>Scap</it>, <it>Srebf2</it>), indicating profound dysregulation of cholesterol homeostasis.</p> <p>Conclusions</p> <p>Acute loss of mitochondrial function, and in particular Δψ<sub>m</sub>, reduces cholesterol efflux to apoA-I and dysregulates macrophage cholesterol homeostasis mechanisms. Bioavailable antioxidants, targeted to mitochondria and capable of sustaining effective mitochondrial function, may therefore prove effective in maintenance of arterial health.</p
Pd-Catalyzed Enantioselective Hydroalkoxylation of Alkoxyallenes with Phenol for Construction of Acyclic O
Morphological and compositional characterization of copper-cobalt spinel made by mechanochemical reactions
Syntheses, Structure, and Bonding of Rb14(Mg1-xInx)30. A Nonstoichiometric Phase with an Unusual Substitution in the Anion Framework
A 8Tl11 (A = K, Rb, or Cs) phases with hypoelectronic Tl11 7? cluster anions: Syntheses, structure, bonding, and properties
Hydrothermal Synthesis and Characterization of an Ethylenediamine-Templated Mixed-Valence Titanium Phosphate
Nanometer superstructure in liquid alkali-thallium alloys
Structure factors obtained from neutron diffraction measurements on liquid K-Tl and Cs-Tl alloys exhibit large prepeaks at approximately 0.77 angstrom-1 and 0.70 angstrom-1, respectively. It is concluded that the liquid contains large units of thallium atoms, possibly bearing some resemblance to those found in crystalline K8Tl11
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