PPARγ Deacetylation Confers the Antiatherogenic Effect and Improves Endothelial Function in Diabetes Treatment.

Autor:	Liu L; Naomi Berrie Diabetes Center, Columbia University, New York, NY.; Department of Pathology and Cell Biology, Columbia University, New York, NY., Fan L; Naomi Berrie Diabetes Center, Columbia University, New York, NY.; Department of Pathology and Cell Biology, Columbia University, New York, NY.; Department of Cardiology, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, Shanxi, China., Chan M; Department of Biological Sciences, Columbia University, New York, NY., Kraakman MJ; Naomi Berrie Diabetes Center, Columbia University, New York, NY.; Department of Medicine, Columbia University, New York, NY., Yang J; Naomi Berrie Diabetes Center, Columbia University, New York, NY.; Department of Pathology and Cell Biology, Columbia University, New York, NY.; Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, Shanxi, China., Fan Y; Naomi Berrie Diabetes Center, Columbia University, New York, NY.; Department of Pathology and Cell Biology, Columbia University, New York, NY., Aaron N; Naomi Berrie Diabetes Center, Columbia University, New York, NY.; Department of Pharmacology, Columbia University, New York, NY., Wan Q; Naomi Berrie Diabetes Center, Columbia University, New York, NY.; Department of Pathology and Cell Biology, Columbia University, New York, NY., Carrillo-Sepulveda MA; Department of Biomedical Sciences, College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, NY., Tall AR; Department of Medicine, Columbia University, New York, NY., Tabas I; Department of Medicine, Columbia University, New York, NY., Accili D; Naomi Berrie Diabetes Center, Columbia University, New York, NY.; Department of Medicine, Columbia University, New York, NY., Qiang L; Naomi Berrie Diabetes Center, Columbia University, New York, NY lq2123@cumc.columbia.edu.; Department of Pathology and Cell Biology, Columbia University, New York, NY.
Jazyk:	angličtina
Zdroj:	Diabetes [Diabetes] 2020 Aug; Vol. 69 (8), pp. 1793-1803. Date of Electronic Publication: 2020 May 14.
DOI:	10.2337/db20-0217
Abstrakt:	Cardiovascular disease (CVD) is the leading cause of death in patients with diabetes, and tight glycemic control fails to reduce the risk of developing CVD. Thiazolidinediones (TZDs), a class of peroxisome proliferator-activated receptor γ (PPARγ) agonists, are potent insulin sensitizers with antiatherogenic properties, but their clinical use is limited by side effects. PPARγ deacetylation on two lysine residues (K268 and K293) induces brown remodeling of white adipose tissue and uncouples the adverse effects of TZDs from insulin sensitization. Here we show that PPARγ deacetylation confers antiatherogenic properties and retains the insulin-sensitizing effects of TZD while circumventing its detriments. We generated mice homozygous with mice with deacetylation-mimetic PPARγ mutations K268R/K293R (2KR) on an LDL-receptor knockout ( Ldlr -/- ) background. 2KR:Ldlr -/- mice showed smaller atherosclerotic lesion areas than Ldlr -/- mice, particularly in aortic arches. With rosiglitazone treatment, 2KR:Ldlr -/- mice demonstrated a residual antiatherogenic response and substantial protection against bone loss and fluid retention. The antiatherosclerotic effect of 2KR was attributed to the protection of endothelium, indicated by improved endothelium-dependent vasorelaxation and repressed expression of proatherogenic factors including inducible nitric oxide synthase, interleukin-6, and NADPH oxidase 2. Therefore, manipulating PPARγ acetylation is a promising therapeutic strategy to control risk of CVD in diabetes treatment. (© 2020 by the American Diabetes Association.)
Databáze:	MEDLINE
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