PPARγ Deacetylation: A Novel Therapeutic Strategy to Mitigate Arterial Stiffness in Obese Male Mice

• Published in: The FASEB journal 2022-05, Vol.36 (S1), p.n/a
• Main Authors: Kiernan, Risa N., Perez, Alexis, Yuen, Amanda, Carrillo‐Sepulveda, Maria Alicia
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.2022.36.S1.R2029

Background Obesity has become a worldwide epidemic and is a major risk factor for the development of cardiovascular disease (CVD). Stiffening in the large arteries, such as the aorta, is a prevalent complication in obesity and frequently precedes hypertension. The mechanism by which obesity contributes to arterial stiffness remains unclear. Peroxisome proliferator‐activated receptor gamma (PPARγ) is a known vasculo‐protective factor. Post‐translational modifications of PPARγ by acetylation can regulate its function. Recently, our group identified that deacetylation of PPARγ enhances vascular endothelial function. We hypothesize that deacetylation of PPARγ protects against obesity‐related arterial stiffness. Methods A mice model of Western diet (WD) induced obesity and our model of deacetylated PPARγ mimetic knock‐in mice with a double lysine to arginine mutation (Lys268Arg, Lys293Arg, termed 2KR mice) were utilized. Adult male C57BL/6 and 2KR mice were randomized into two dietary protocols. Control groups of C57BL/6 (n=8) and 2KR mice (n=5) received a regular chow diet (5% fat, 48.7% carbohydrates [3.2% sucrose], and 24.1% protein) for 24 weeks. WD groupsof C5 7BL/6 (n=10) and 2KR mice (n= 5) received a WD (40% fat, 43% carbohydrates [34% sucrose], and 17% protein) for 24 weeks. Metabolic profiles were assessed by using single‐mouse‐sized metabolic cages. Aortic stiffness was assessed by measuring pulse wave velocity (PWV) with high‐resolution ultrasound, the gold standard for arterial stiffness. Systolic blood pressure was measured using tail cuff plethysmography. Results WD‐induced obesity was confirmed by increased body weight in both WD C57BL/6 mice (36.5g vs. 28.6g controls, p