Disruption of endothelial peroxisome proliferator-activated receptor ? accelerates diet-induced atherogenesis in LDL receptor-null mice.

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

SUBMITTER: Qu A 

PROVIDER: S-EPMC3649072 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature