Abstract 262: Dominant Negative PPARG Influences Atherosclerosis Through Distinct Effects in Vascular Endothelium and Smooth Muscle

Abstract

Agonists of the nuclear hormone receptor PPARγ inhibit atherosclerosis progression; however, direct actions of PPARγ in the vessel wall during atherosclerosis remain undefined. We reported that transgenic mice expressing dominant negative (DN) PPARγ targeted to the vascular endothelium (E-DN) or smooth muscle (S-DN) on the apolipoprotein E-deficient (ApoE -/- ) background exhibit increased diet-induced atherosclerotic lesion area in aorta compared to non-transgenic (NT) control mice without changes in plasma cholesterol or triglycerides. Here we show that abdominal aortic rings from standard diet-fed E-DN.ApoE -/- mice display impaired endothelium-dependent relaxation in response to Ach (3μM: 44±2% vs 72±1% in NT.ApoE -/- ; P<0.05) despite normal relaxation to SNP (1μM: 85±1% vs 85±2%; NS) and contraction in response to ET-1 (30nM: 0.84±0.13g vs 0.75±0.08g; NS) and Ang II (10nM: 0.33±0.03g vs 0.33±0.04g; NS). In contrast, abdominal aortic rings from S-DN.ApoE -/- mice display impaired nitric oxide-dependent relaxation in response to Ach (3μM: 47±3% vs 71±1% in NT.ApoE -/- ; P<0.05) and SNP (1μM: 57±3% vs 84±2%; P<0.05) plus enhanced contraction to ET-1 (30nM: 0.98±0.05g vs 0.71±0.12g; P<0.05) and Ang II (10nM: 0.49±0.06g vs 0.36±0.03g; P<0.05). Systolic blood pressure was elevated in E-DN.ApoE -/- mice (127±3 vs 112±2 mmHg in NT.ApoE -/- ; P<0.05) and S-DN.ApoE -/- mice (123±1 vs 109±2 mmHg in NT.ApoE -/- ; P<0.05). Analyzed by real-time qPCR, aorta from E-DN.ApoE -/- mice had increased mRNA expression of Mcp1 (1.68±0.26-fold of NT.ApoE -/- ; P<0.05) and decreased expression of Catalase (0.59±0.13-fold; P<0.05) and Cd36 (0.69±0.09-fold; P<0.05), while Cd68 , Icam1 , Tnfα , Osteopontin , and Vcam1 were not changed. Aorta from S-DN.ApoE -/- mice had increased mRNA expression of Mcp1 (1.75±0.23-fold of NT.ApoE -/- ; P<0.05), Osteopontin (2.18±0.13-fold; P<0.05) and Vcam1 (1.87±0.24-fold; P<0.05) and decreased expression of Cd36 (0.72±0.08-fold; P<0.05), while Cd68 , Icam1 , Tnfα , and Catalase were not changed. In summary, endothelial- or smooth muscle-specific DN PPARγ induces distinct alterations in vascular function and atherogenic markers. Inhibition of PPARγ function in the vessel wall may contribute to cardiovascular disease.