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.


RESULTS
To assess the contribution of endothelial-specific PPARγ in atherosclerosis, EC-specific PPARγ disruption and LDL receptor (LDLR) double-knockout (PPARγ(ΔEC)/LDLR(-/-)) mice were developed. When challenged with a high-cholesterol diet for 4 weeks, PPARγ(ΔEC)/LDLR(-/-) mice exhibited severe atherosclerotic lesions compared to either their littermate controls or macrophage-specific PPARγ disruption and LDLR double knockout (PPARγ(ΔMΦ)/LDLR(-/-)) mice. Metabolic analysis showed severe dyslipidemia and significant increase in systolic blood pressure in the PPARγ(ΔEC)/LDLR(-/-) mice. Histological analysis and real-time quantitative PCR suggested an exacerbated inflammation in PPARγ(ΔEC)/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.


CONCLUSIONS
Endothelial PPARγ plays an important protective role in atherogenesis.
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20814, USA.
Aijuan
A
Qu
Yatrik M
YM
Shah
Soumen K
SK
Manna
Frank J
FJ
Gonzalez
D000818:Animals; D050197:Atherosclerosis / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D001794:Blood Pressure / Q000502:physiology; D016026:Bone Marrow Transplantation; D002199:Capillary Permeability / Q000502:physiology; D002784:Cholesterol / Q000097:blood; D004036:Diet, Atherogenic / Q000009:adverse effects; D042783:Endothelial Cells / Q000502:physiology; D007249:Inflammation / Q000209:etiology; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047495:PPAR gamma / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D014280:Triglycerides / Q000097:blood
D047495:PPAR gamma; D011973:Receptors, LDL; D014280:Triglycerides; D002784:Cholesterol