PPARγ Deacetylation Confers the Antiatherogenic Effect and Improves Endothelial Function in Diabetes Treatment
| Autor: | Maria Alicia Carrillo-Sepulveda, Longhua Liu, Michelle Chan, Michael J Kraakman, Li Qiang, Nicole Aaron, Lihong Fan, Ira Tabas, Qianfen Wan, Yong Fan, Alan R. Tall, Domenico Accili, Jing Yang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Complications Endothelium Endocrinology Diabetes and Metabolism medicine.medical_treatment Blotting Western Nitric Oxide Synthase Type II 030209 endocrinology & metabolism White adipose tissue Real-Time Polymerase Chain Reaction 03 medical and health sciences Diabetes mellitus genetics Mice 0302 clinical medicine Diabetes mellitus Internal medicine Internal Medicine medicine Diabetes Mellitus Animals Mice Knockout NADPH oxidase biology Chemistry Interleukin-6 Insulin medicine.disease Atherosclerosis Nitric oxide synthase PPAR gamma 030104 developmental biology medicine.anatomical_structure Endocrinology Receptors LDL Mutation NADPH Oxidase 2 biology.protein Thiazolidinediones Rosiglitazone medicine.drug Chromatography Liquid |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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