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Ablation of the three genes encoding isoforms of FOXO in endothelial cells prevents atherosclerosis in LDL receptor knockout mice. Mice bearing constitutively deacetylated alleles of Foxo1 develop larger artherosclerotic lesions despite improved plasma lipid levels. Deacetylation of FOXO1 leads to its activation and enhanced expression of FOXO1 target genes. FOXO1 activity is regulated through processes of phosphorylation by Akt, acetylation at multiple lysine residues and deacetylation by several deacetylases, including the NAD +-dependent deacetylase SIRT1 -.įOXO1 is deacetylated in response to oxidative stress and hyperglycemia. įOXO1 is strongly expressed in atherosclerotic plaques, regulates expression of different cell cycle regulators and is involved in multiple atherogenic pathways in endothelial cells.
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Moreover, SIRT1 is a key component in several stress-responsive pathways involved in apoptotic cell death and cellular senescence. In vascular smooth muscle cells SIRT1 enhances the activity of tissue inhibitor of metalloproteinase 3 that might stabilize atherosclerotic plaques. In endothelial cells and macrophages SIRT1 has anti-inflammatory functions by down-regulating the expression of various pro-inflammatory cytokines, interfering with the NFκB signaling pathway, preventing macrophage foam cell formation and suppressing of endothelial tissue factor (coagulation factor III) expression. It controls vascular tone and endothelial function by deacetylation of endothelial nitric oxide synthase and by stimulating its activity. SIRT1 seems to have protective properties against atherosclerosis. Recently, their role in vascular homeostasis has been suggested. SIRT1 and FOXO1 are evolutionary conserved regulators of aging, metabolic processes and resistance to oxidative stress. This study demonstrated associations of genetic variations at the SIRT1 and FOXO1 loci with carotid atherosclerosis and highlighted the need for further investigation by functional studies. The latter was significant in women only (beta women = 0.111, p women = 0.00008 beta men = -0.009, p men = 0.6464). Several SNPs within SIRT1 showed differential effects for men and women with higher effect sizes for women: rs3740051 on all three investigated phenotypes (interaction p-value < 0.0069) rs2236319 on common and internal carotid IMT (interaction p-value < 0.0083), rs10823108, rs2273773 on common carotid IMT and rs1467568 on B-score (interaction p-value = 0.0007). One haplotype in FOXO1 showed a moderate effect on common carotid IMT and B-score in comparison to the reference haplotype of this gene. Analysis for internal carotis IMT and B-score did not reveal any significant association. Additional adjustment for traditional cardiovascular risk factors and markers (BMI, smoking status, hypertension, total cholesterol, HDL-cholesterol, hsCRP) even improved the strength of this association (p = 0.0037 for SIRT1 and p = 0.0002 for both SNPs at FOXO1). ResultsĪ significant association was found between common carotid IMT and two SNPs at FOXO1 - rs10507486, rs2297627 (beta = -0.00168, p = 0.0007 and beta = -0.00144, p = 0.0008 respectively) and at least a trend for rs12413112 at SIRT1 (beta = 0.00177, p = 0.0157) using an additive model adjusting for age and sex.
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The association of each SNP with common carotid IMT, internal carotid IMT and B-score was analyzed using linear regression models. Eleven SNPs at SIRT1 and FOXO1 gene loci were genotyped in the SAPHIR cohort (n = 1742). Morphological alterations of the carotid arteries and size of these alterations were included in the B-score grading on a five point scale. Intima-media thickness (IMT) was measured on the common and internal carotid arteries. It is not known, if genetic polymorphisms (SNPs) at the SIRT1 and FOXO1 have an influence on carotid atherosclerosis.
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SIRT1 and FOXO1 interact with each other in multiple pathways regulating aging, metabolism and resistance to oxidative stress and control different pathways involved in atherosclerotic process.