title: Increased atherosclerosis and endothelial dysfunction in mice bearing constitutively deacetylated alleles of Foxo1 gene.
abstract: Complications of atherosclerosis are the leading cause of death of patients with type 2 (insulin-resistant) diabetes. Understanding the mechanisms by which insulin resistance and hyperglycemia contribute to atherogenesis in key target tissues (liver, vessel wall, hematopoietic cells) can assist in the design of therapeutic approaches. We have shown that hyperglycemia induces FoxO1 deacetylation and that targeted knock-in of alleles encoding constitutively deacetylated FoxO1 in mice (Foxo1(KR/KR)) improves hepatic lipid metabolism and decreases macrophage inflammation, setting the stage for a potential anti-atherogenic effect of this mutation. Surprisingly, we report here that when Foxo1(KR/KR) mice are intercrossed with low density lipoprotein receptor knock-out mice (Ldlr(-/-)), they develop larger aortic root atherosclerotic lesions than Ldlr(-/-) controls despite lower plasma cholesterol and triglyceride levels. The phenotype is unaffected by transplanting bone marrow from Ldlr(-/-) mice into Foxo1(KR/KR) mice, indicating that it is independent of hematopoietic cells and suggesting that the primary lesion in Foxo1(KR/KR) mice occurs in the vessel wall. Experiments in isolated endothelial cells from Foxo1(KR/KR) mice indicate that deacetylation favors FoxO1 nuclear accumulation and exerts target gene-specific effects, resulting in higher Icam1 and Tnfα expression and increased monocyte adhesion. The data indicate that FoxO1 deacetylation can promote vascular endothelial changes conducive to atherosclerotic plaque formation.
authors.affiliation: Berrie Diabetes Center and Department of Medicine, Columbia University, New York, New York 10032, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Qiang
authors.forename: Kyoichiro
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Ja-Young
authors.initials: JY
authors.lastname: Kim-Muller
authors.forename: Hua V
authors.initials: HV
authors.lastname: Lin
authors.forename: Carrie
authors.initials: C
authors.lastname: Welch
authors.forename: Domenico
authors.initials: D
authors.lastname: Accili
mesh_terms: D000107:Acetylation; D000483:Alleles; D000818:Animals; D017209:Apoptosis; D050197:Atherosclerosis / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D003920:Diabetes Mellitus / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology; D004730:Endothelium, Vascular / Q000473:pathology*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D007249:Inflammation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018384:Oxidative Stress; D015398:Signal Transduction
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse