Disruption of Endothelial Peroxisome Proliferator-Activated Receptor γ Accelerates Diet-Induced Atherogenesis in LDL Receptor-Null Mice

Objective-Peroxisome proliferator-activated receptor gamma (PPAR gamma) 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) PPAR gamma in atherogenesis is not fully understood. Methods and Results-To assess the contribution of endothelial-specific PPAR gamma in atherosclerosis, EC-specific PPAR gamma disruption and LDL receptor (LDLR) double-knockout (PPAR gamma(Delta EC)/LDLR-/-) mice were developed. When challenged with a high-cholesterol diet for 4 weeks, PPAR gamma(Delta EC)/LDLR-/- mice exhibited severe atherosclerotic lesions compared to either their littermate controls or macrophage-specific PPAR gamma disruption and LDLR double knockout (PPAR gamma(Delta M Phi)/LDLR-/-) mice. Metabolic analysis showed severe dyslipidemia and significant increase in systolic blood pressure in the PPAR gamma(Delta EC)/LDLR-/- mice. Histological analysis and real-time quantitative PCR suggested an exacerbated inflammation in PPAR gamma(Delta EC)/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 PPAR gamma disruption. Bone-marrow transplantation studies, which reconstituted hematopoietic PPAR gamma, demonstrated that the accelerated atherogenesis was due to endothelial PPAR gamma deficiency. Conclusion-Endothelial PPAR gamma plays an important protective role in atherogenesis. (Arterioscler Thromb Vasc Biol. 2012;32:65-73.)