tretinoin and 7-ketocholesterol

Methionine sulfoxide reductase B2 (MSRB2) is a mitochondrial enzyme that converts methionine sulfoxide (R) enantiomer back to methionine. This enzyme is suspected of functioning to protect mitochondrial proteins from oxidative damage. In this study we report that the retina is one of the human tissues with highest levels of MSRB2 mRNA expression. Other tissues with high expression were heart, kidney and skeletal muscle. Overexpression of an MSRB2-GFP fusion protein increased the MSR enzymatic activity three-fold in stably transfected cultured RPE cells. This overexpression augmented the resistance of these cells to the toxicity induced by 7-ketocholesterol, tert-butyl hydroperoxide and all-trans retinoic acid. By contrast, knockdown of MSRB2 by a miRNA in stably transfected cells did not convey increased sensitivity to the oxidative stress. In the monkey retina MSRB2 localized to the ganglion cell layer (GLC), the outer plexiform layer (OPL) and the retinal pigment epithelium (RPE). MSRB2 expression is most pronounced in the OPL of the macula and foveal regions suggesting an association with the cone synaptic mitochondria. Our data suggests that MSRB2 plays an important function in protecting cones from multiple type of oxidative stress and may be critical in preserving central vision.

Topics: Animals; Cell Survival; Cells, Cultured; Chromatography, High Pressure Liquid; Cytoprotection; Enzyme Inhibitors; Female; Gene Expression Regulation, Enzymologic; Gene Silencing; Green Fluorescent Proteins; Humans; Ketocholesterols; Kidney; Macaca mulatta; Methionine Sulfoxide Reductases; Microfilament Proteins; Muscle, Skeletal; Myocardium; Oxidative Stress; Oxidoreductases; Recombinant Fusion Proteins; Retina; Retinal Cone Photoreceptor Cells; Retinal Pigment Epithelium; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; tert-Butylhydroperoxide; Transcription Factors; Transfection; Tretinoin

We studied the effects of cholesterol, its oxidized derivatives mevalonate, and nuclear receptor agonists LXR, RXR, and FXR on the production of transforming growth factor-beta1 (TGF- beta1) by macrophages. After recruiting of macrophage monocytes into the focus of inflammation, the production of TGF-beta1 increased by 3.5 times in comparison with control macrophages. Cholesterol diet stimulated the production of TGF-beta1 by 2.5 times. Cholesterol directly stimulated macrophage production of TGF-beta1 in vitro, while addition of mevalonate to the incubation medium effectively reduced this induced production. Agonists of nuclear receptor sharply reduced the production of TGF-beta1 in recruited macrophages. Under conditions of inflammation, hypercholesterolemia can be a factor of fibrogenesis due to TGF-beta1 induction in macrophages, which depends on the products of mevalonate biochemical chain.

Topics: Alitretinoin; Animals; Cells, Cultured; Cholesterol; Farnesol; Hydroxycholesterols; Hydroxysteroids; Ketocholesterols; Lipopolysaccharides; Liver X Receptors; Macrophages; Male; Mevalonic Acid; Mice; Mice, Inbred C57BL; Orphan Nuclear Receptors; Receptors, Cytoplasmic and Nuclear; Retinoid X Receptors; Transforming Growth Factor beta; Tretinoin