Activation of TGF-β receptors and Smad proteins by atorvastatin is related to reduced atherogenesis in ApoE/LDLR double knockout mice
Language English Country Japan Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
22104174
DOI
10.5551/jat.8185
PII: JST.JSTAGE/jat/8185
Knihovny.cz E-resources
- MeSH
- Anticholesteremic Agents therapeutic use MeSH
- Apolipoproteins E physiology MeSH
- Atherosclerosis metabolism prevention & control MeSH
- Atorvastatin MeSH
- Cholesterol metabolism MeSH
- Endoglin MeSH
- Immunoenzyme Techniques MeSH
- Intracellular Signaling Peptides and Proteins metabolism MeSH
- Heptanoic Acids therapeutic use MeSH
- Receptors, LDL physiology MeSH
- Mice, Inbred C57BL MeSH
- Mice, Knockout MeSH
- Mice MeSH
- Smad1 Protein metabolism MeSH
- Smad2 Protein metabolism MeSH
- Protein Serine-Threonine Kinases metabolism MeSH
- Pyrroles therapeutic use MeSH
- Receptors, Transforming Growth Factor beta metabolism MeSH
- Nitric Oxide Synthase Type III metabolism MeSH
- Receptor, Transforming Growth Factor-beta Type I MeSH
- Vascular Endothelial Growth Factor A metabolism MeSH
- Blotting, Western MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Anticholesteremic Agents MeSH
- Apolipoproteins E MeSH
- Atorvastatin MeSH
- Cholesterol MeSH
- Endoglin MeSH
- Eng protein, mouse MeSH Browser
- Intracellular Signaling Peptides and Proteins MeSH
- Heptanoic Acids MeSH
- Receptors, LDL MeSH
- Nos3 protein, mouse MeSH Browser
- Smad1 Protein MeSH
- Smad2 Protein MeSH
- Protein Serine-Threonine Kinases MeSH
- Pyrroles MeSH
- Receptors, Transforming Growth Factor beta MeSH
- Smad1 protein, mouse MeSH Browser
- Smad2 protein, mouse MeSH Browser
- Nitric Oxide Synthase Type III MeSH
- Receptor, Transforming Growth Factor-beta Type I MeSH
- Tgfbr1 protein, mouse MeSH Browser
- vascular endothelial growth factor A, mouse MeSH Browser
- Vascular Endothelial Growth Factor A MeSH
AIM: Transforming growth factor-beta (TGF-β) plays important role in atherogenesis via TGF-β receptors and Smad proteins, which determine its signaling activity. In this study, we hypothesized, whether non-lipid related effects of atorvastatin, affect both endoglin/ALK-5/Smad2/eNOS and/or endoglin/ALK-1/Smad1/VEGF previously proposed pathways in ApoE/LDLR double knockout mice. METHODS: ApoE/LDLR double knockout mice were divided into two groups. The chow group (CHOW) (n =8) was fed with chow diet, while in the atorvastatin group (ATV) (n =8) atorvastatin was added to the chow diet at dose 50 mg/kg/day. Biochemical analyses of lipid profile, lesion area measurement, immunohistochemistry and Western blot analysis of endoglin, ALK-1, 5, phosphorylated and non-phosphorylated forms Smad-1, 2, VEGF and eNOS proteins in mice aorta were performed. RESULTS: Biochemical analysis of blood serum and morphometric analysis of aortic lesion size showed that atorvastatin treatment resulted in a significant increase of cholesterol levels and simultaneously in reduced lesion size in aortic sinus when compared to CHOW mice. Western blot analysis revealed that atorvastatin treatment significantly increase the expressions of endoglin by 102%, ALK-1 by 113%, ALK-5 by 296%, pSmad-1 by 202%, pSmad-2 by 34%, VEGF by 68% and eNOS by 687% as compared with CHOW mice. Immunofluorescence staining revealed endoglin coexpression with all studied markers that were increased by atorvastatin treatment mainly in endothelial cells covering atherosclerotic plaques. CONCLUSION: This study shows that atorvastatin treatment increases the expression of endoglin, ALK-1, ALK-5, phosphorylated forms of Smad1 and Smad2, VEGF and eNOS and reduces atherosclerotic lesion size beyond its lipid lowering effects. Therefore, we propose that endoglin related receptors and signal transducers might play protective role in atherogenesis.
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