Disruption of Endothelial Peroxisome Proliferator-Activated Receptor γ Accelerates Diet-Induced Atherogenesis in LDL Receptor-Null Mice
Objective—Peroxisome proliferator-activated receptor γ (PPARγ) is widely expressed in vessel walls, and it's activation by agonists showed beneficial effects in cardiovascular diseases. However, the role of endothelial cell (EC) PPARγ in atherogenesis is not fully understood.
Methods and Results—To assess the contribution of endothelial-specific PPARγ in atherosclerosis, we developed EC-specific PPARγ disruption and LDL receptor (LDLR) double-knockout (PPARγΔEC/LDLR−/−) mice were developed. When challenged with a high-cholesterol diet for 4 weeks, PPARγΔEC/LDLR−/− mice exhibited severe atherosclerotic lesions compared to either their littermate controls or macrophage-specific PPARγ disruption and LDLR double knockout (PPARγΔMφ/LDLR−/−) mice. Metabolic analysis showed severe dyslipidemia and significant increase in systolic blood pressure (BP) in the PPARγΔMφ/LDLR−/− mice. Histological analysis and real-time quantitative PCR suggested an exacerbated inflammation in PPARγΔEC/LDLR−/− mice, as revealed by the increases of proinflammatory gene expression and macrophage infiltration in vivo and in vitro. Furthermore, in vivo endothelial permeability was also increased by endothelial PPARγ disruption. Bone-marrow transplantation studies, which reconstituted hematopoietic PPARγ, demonstrated that the accelerated atherogenesis was due to endothelial PPARγ deficiency.
Conclusion—Endothelial PPARγ plays an important protective role in atherogenesis.
- Received May 6, 2011.
- Accepted October 5, 2011.
- © 2011 American Heart Association, Inc.