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

Abstract

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<0.001) and WD 2KR mice groups (44.7g vs. 29.86g controls, p<0.0001). Results obtained from metabolic cages revealed reduction in food, energy and water intake, and urine and fecal output in the WD C57BL/6 and WD 2KR groups as compared to their respective controls. These results indicate that weight gain in WD‐fed mice is not explained by increased energy intake, but rather a reduced metabolic rate. As expected, the WD C57BL/6 group exhibited increased aortic stiffness (5.4 m/s vs. 4.1 m/s controls, p<0.05), which was accompanied by elevated systolic blood pressure (143.8 ± 1.66 vs. 123.5 ± 4.76 mmHg controls, p<0.05). Strikingly, while WD 2KR mice developed obesity, these mice did not exhibit increased aortic stiffness (4.3 m/s vs. 4/4 m/s controls, p=0.89) nor elevated systolic blood pressures (122.4 ± 3.93 mmHg vs. x 115.2 ± 4.15 mmHg controls, p=0.26), indicating that deacetylation of PPARγ protects against aortic stiffness and increases in arterial blood pressure in obesity. Conclusions Our findings demonstrate that while deacetylation of PPARγ does not prevent the development of WD‐induced obesity, it does protect against arterial stiffness in obesity. These results indicate that PPARγ deacetylation is a potential therapeutic strategy in the prevention of obesity‐related arterial stiffness.