Activation of TGF-β receptors and Smad proteins by atorvastatin is related to reduced atherogenesis in ApoE/LDLR double knockout mice
Jazyk angličtina Země Japonsko Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
22104174
DOI
10.5551/jat.8185
PII: JST.JSTAGE/jat/8185
Knihovny.cz E-zdroje
- MeSH
- anticholesteremika terapeutické užití MeSH
- apolipoproteiny E fyziologie MeSH
- ateroskleróza metabolismus prevence a kontrola MeSH
- atorvastatin MeSH
- cholesterol metabolismus MeSH
- endoglin MeSH
- imunoenzymatické techniky MeSH
- intracelulární signální peptidy a proteiny metabolismus MeSH
- kyseliny heptylové terapeutické užití MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- protein Smad1 metabolismus MeSH
- protein Smad2 metabolismus MeSH
- protein-serin-threoninkinasy metabolismus MeSH
- pyrroly terapeutické užití MeSH
- receptory LDL fyziologie MeSH
- receptory transformujícího růstového faktoru beta metabolismus MeSH
- synthasa oxidu dusnatého, typ III metabolismus MeSH
- TGF-beta receptor I. typu MeSH
- vaskulární endoteliální růstový faktor A metabolismus MeSH
- western blotting MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- anticholesteremika MeSH
- apolipoproteiny E MeSH
- atorvastatin MeSH
- cholesterol MeSH
- endoglin MeSH
- Eng protein, mouse MeSH Prohlížeč
- intracelulární signální peptidy a proteiny MeSH
- kyseliny heptylové MeSH
- Nos3 protein, mouse MeSH Prohlížeč
- protein Smad1 MeSH
- protein Smad2 MeSH
- protein-serin-threoninkinasy MeSH
- pyrroly MeSH
- receptory LDL MeSH
- receptory transformujícího růstového faktoru beta MeSH
- Smad1 protein, mouse MeSH Prohlížeč
- Smad2 protein, mouse MeSH Prohlížeč
- synthasa oxidu dusnatého, typ III MeSH
- TGF-beta receptor I. typu MeSH
- Tgfbr1 protein, mouse MeSH Prohlížeč
- vascular endothelial growth factor A, mouse MeSH Prohlížeč
- vaskulární endoteliální růstový faktor 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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