ascorbic-acid and mevastatin

Deregulated crosstalk within nuclear receptor/transcription factor family, comprising of peroxisome proliferator-activated receptors (PPARs) and liver X receptor-alpha (LXR-alpha), can give rise to cooperativity between lipid peroxidation and inflammation leading to atherogenic process. The present study addressed to explore the effect of statins and vitamin 'C' on transcriptional expression of genes coding for this nuclear receptor/transcription factor family within mononuclear cells revealed for the first time that both mevastatin and vitamin 'C' have common action in that they significantly downregulate the expression of PPARs (alpha, gamma) genes and upregulate LXR-alpha gene expression as compared to the control. The similar phenomenon was observed in mononuclear cells obtained from coronary heart disease (CHD) patients who were receiving atorvastatin treatment (20 mg HS). Further, the observed upregulatory effect of LXR-alpha gene expression was in conformity with the downregulatory effect of LXR-alpha on its effector gene matrix metalloproteinase-9. Based on these results, we propose that LXR-alpha-dependent signaling pathway may be a crucial target for the therapeutic intervention in human CHD, and in addition to statins, vitamin 'C' deserves a close scrutiny for the treatment of CHD.

Topics: Animals; Arteriosclerosis; Ascorbic Acid; DNA-Binding Proteins; Free Radical Scavengers; Gene Expression Regulation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Leukocytes, Mononuclear; Lipid Peroxidation; Liver X Receptors; Lovastatin; Molecular Sequence Data; Orphan Nuclear Receptors; Peroxisome Proliferator-Activated Receptors; Receptors, Cytoplasmic and Nuclear; Reverse Transcriptase Polymerase Chain Reaction

Embryonic stem (ES) cells have the capacity to differentiate into various cell types in vitro. In this study, we show that retinoic acid is important for the commitment of ES cells into osteoblasts. Culturing retinoic acid treated ES cells in the presence of the osteogenic supplements ascorbic acid and beta-glycerophosphate resulted in the expression of several osteoblast marker genes, osteocalcin, alkaline phosphatase, and osteopontin. However, there was only a slight amount of mineralized matrix secretion. Addition of bone morphogenic protein-2 or compactin, a drug of the statin family of HMG-CoA reductase inhibitors, resulted in a greatly enhanced formation of bone nodules. Compactin did not modify the expression of osteogenic markers, but at the late stage of differentiation promoted an increase in BMP-2 expression. These results establish ES-cell derived osteogenesis as an effective model system to study the molecular mechanisms by which the statin compactin promotes osteoblastic differentiation and bone nodule formation.

Topics: Alkaline Phosphatase; Animals; Antigens, Differentiation; Ascorbic Acid; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Cell Differentiation; Cells, Cultured; Glycerophosphates; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lovastatin; Mice; Osteoblasts; Osteocalcin; Osteogenesis; Osteopontin; RNA, Messenger; Sialoglycoproteins; Stem Cells; Transforming Growth Factor beta; Tretinoin