phytosterols and Aortic-Diseases

Inflammation is triggered after invasion or injury to restore homeostasis. Although the activation of Wnt/β-catenin signaling is one of the first molecular responses to cellular damage, its role in inflammation is still unclear. It was our hypothesis that the low-density lipoprotein (LDL) receptor-related protein 5 (LRP5) and the canonical Wnt signaling pathway are modulators of inflammatory mechanisms. Wild-type (WT) and LRP5(-/-) mice were fed a hypercholesterolemic (HC) diet to trigger dislipidemia and chronic inflammation. Diets were supplemented with plant sterol esters (PSEs) to induce LDL cholesterol lowering and the reduction of inflammation. HC WT mice showed increased serum cholesterol levels that correlated with increased Lrp5 and Wnt/β-catenin gene expression while in the HC LRP5(-/-) mice Wnt/β-catenin pathway was shut down. Functionally, HC induced pro-inflammatory gene expression in LRP5(-/-) mice, suggesting an inhibitory role of the Wnt pathway in inflammation. Dietary PSE administration downregulated serum cholesterol levels in WT and LRP5(-/-) mice. Furthermore, in WT mice PSE increased anti-inflammatory genes expression and inhibited Wnt/β-catenin activation. Hepatic gene expression of Vldlr, Lrp2 and Lrp6 was increased after HC feeding in WT mice but not in LRP5(-/-) mice, suggesting a role for these receptors in the clearance of plasmatic lipoproteins. Finally, an antiatherogenic role for LRP5 was demonstrated as HC LRP5(-/-) mice developed larger aortic atherosclerotic lesions than WT mice. Our results show an anti-inflammatory, pro-survival role for LRP5 and the Wnt signaling pathway in peripheral blood leukocytes.

Topics: Animals; Aorta; Aortic Diseases; Atherosclerosis; ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP Binding Cassette Transporter, Subfamily G, Member 8; ATP-Binding Cassette Transporters; Cholesterol; Cholesterol, Dietary; Cholesterol, HDL; Humans; Hypercholesterolemia; Jejunum; Leukocytes; Lipoproteins; Liver; Low Density Lipoprotein Receptor-Related Protein-5; Macrophages; Mice; Mice, Inbred C57BL; Monocytes; Phytosterols; RNA Interference; RNA, Messenger; RNA, Small Interfering; Spleen; Wnt Signaling Pathway

We sought to identify novel atherosclerosis-modifying loci and their potential functional links in a genome-wide approach using cosegregation analysis of atherosclerosis and related intermediate phenotypes in mice.. We carried out an F2 intercross between atherosclerosis-susceptible C57BL/6 mice and atherosclerosis-resistant BALB/cByJ mice on the low-density lipoprotein receptor(-/-) background to examine the genetic basis for their differences in atherosclerosis susceptibility. Atherosclerotic lesion size and a comprehensive panel of 61 atherosclerosis-related phenotypes, including plasma levels of lipids, cytokines, and chemokines were measured in 376 F2 mice. Quantitative trait locus mapping revealed a novel significant locus (logarithm of odds, 6.18) for atherosclerosis on proximal mouse chromosome (Chr) 2 (Ath39), which was associated with major variations in lesion size (14%). Plasma very-low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, lanosterol, and phytosterol levels cosegregated with atherosclerosis at this locus. Moreover, these lipid traits showed significant correlations with lesion size, suggesting that they share the same underlying genetic factor. We also describe a second male-specific locus on Chr 8 (Ath40) where atherosclerosis and lipids cosegregated.. Our study revealed new loci for atherosclerosis susceptibility on mouse Chr 2 and 8, which might exert their effects on lesion size via plasma lipid levels.

Topics: Animals; Aortic Diseases; Atherosclerosis; Cholesterol, HDL; Cholesterol, VLDL; Chromosome Segregation; Chromosomes, Mammalian; Cluster Analysis; Crosses, Genetic; Cytokines; Disease Models, Animal; Female; Genetic Association Studies; Genetic Predisposition to Disease; Inflammation Mediators; Lanosterol; Lipids; Lod Score; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Knockout; Phenotype; Phytosterols; Quantitative Trait Loci; Receptors, LDL; Time Factors