Conditional Knockout of Macrophage PPARγIncreases Atherosclerosis in C57BL/6 and Low-Density Lipoprotein Receptor–Deficient Mice

Abstract

Objective-Peroxisome proliferator-activated receptor gamma (PPAR␥) is highly expressed in macrophage-derived foam cells of atherosclerotic lesions, and its expression may have a dramatic impact on atherosclerosis. Methods and Results-To investigate the contribution of macrophage PPAR␥ expression on atherogenesis in vivo, we generated macrophage-specific PPAR␥ knockout (MacPPAR␥KO) mice. C57BL/6 and low-density lipoprotein (LDL) receptor-deficient (LDLR Ϫ/Ϫ ) mice were reconstituted with MacPPAR␥KO or wild-type marrow and challenged with an atherogenic diet. No differences were found in serum lipids between recipients reconstituted with MacPPAR␥KO and wild-type marrow. In contrast, both C57BL/6 and LDLR Ϫ/Ϫ mice transplanted with MacPPAR␥KO marrow had significantly larger atherosclerotic lesions than control recipients. In addition, MacPPAR␥KO3 LDLR Ϫ/Ϫ mice had higher numbers of macrophages in atherosclerotic lesions compared with controls. Peritoneal macrophages isolated from the MacPPAR␥KO mice had decreased uptake of oxidized but not acetylated LDL and showed no changes in either cholesterol efflux or inflammatory cytokine expression. Macrophages from MacPPAR␥KO mice had increased levels of migration and CC chemokine receptor 2 (CCR2) expression compared with wild-type macrophages. Conclusion-Thus, macrophage PPAR␥ deficiency increases atherosclerosis under conditions of mild and severe hypercholesterolemia, indicating an antiatherogenic role for PPAR␥, which may be caused, at least in part, by modulation of CCR2 expression and monocyte recruitment. Key Words: ABCA1 Ⅲ atherosclerosis Ⅲ CCR2 expression Ⅲ cholesterol efflux Ⅲ macrophages Ⅲ scavenger receptor CD36 P eroxisome proliferator-activated receptor gamma (PPAR␥) is a nuclear transcription factor that regulates a large number of genes important in lipid metabolism and inflammation. 1 The receptor is highly expressed in macrophages and macrophage-derived foam cells of atherosclerotic lesions, 2-4 and its expression may critically affect macrophage functions that impact atherosclerosis, including activation, cytokine production, recruitment, and transformation into foam cells.Several studies have shown that the administration of PPAR␥ agonists inhibits the development of atherosclerosis in low-density lipoprotein (LDL) receptor-deficient (LDLR Ϫ/Ϫ ) 5,6 and apolipoprotein E-deficient (apoE Ϫ/Ϫ ) mice. 7 Consistent with this, mice transplanted with bone marrow from a PPAR␥ Ϫ/Ϫ chimera mouse exhibit a significant increase in atherosclerosis. 8 These data all support an antiatherogenic role for macrophage PPAR␥ in atherosclerotic lesion development.It has been assumed that the antiatherogenic effects of macrophage PPAR␥ expression may derive from activation of genes responsible for cholesterol efflux, thus shifting the balance from lipid loading to lipid efflux. 8 Recent studies, however, have not confirmed the role of PPAR␥ ligands in cholesterol efflux by macrophages. 9,10 PPAR␥ may also exert antiinflammatory effects in macrophages directly, 11 or through ...

Downregulation of Peroxisome Proliferator‐activated Receptor‐γ Expression in Hypertensive Atrial Fibrillation

“…13 In fact, the pathophysiology of nonvalvular AF is somewhat different from that of valvular AF, and the former is extremely complex and unclear. It should be emphasized that previous studies did not compare the role of inflammation in valvular AF and nonvalvular AF.…”

“…Several studies have shown that PPARγ is expressed in healthy human coronary arteries, aortic vascular smooth muscle (VSM) cells and heart ventricles. 11, 12 Babaev et al found that conditional knockout of macrophage PPARγ increases atherosclerosis in C57BL/6 (macrophagespecific PPAR gamma knockout mice) and low-density lipoprotein receptor-deficient mice, 13 Adil et al, 14 realized that cardiac and aortic PPARγ expression is modulated by hypertension and oxidative stress in chronically glucosefed rats. Abundant evidences suggest that PPARγ agonists exert cardiovascular antioxidant and anti-inflammatory effects.…”

Nuclear receptors in macrophages: A link between metabolism and inflammation

“…Magnifications: 1000· (A), 250· (B and C), 400· (insert). plasma and HDL cholesterol levels and cholesterol efflux was significantly decreased from macrophages elicited by thioglycolate in mutant mice [18,19].…”

Differential Roles of Cardiomyocyte and Macrophage Peroxisome Proliferator–Activated Receptor γ in Cardiac Fibrosis

“…(mPPAR␥ Ϫ/Ϫ ) mice, previously described by Babaev et al (33), were thus analyzed using the same treatment protocol to address the role of macrophage PPAR␥ in cardiac cardiac fibrosis increases, which were substantially greater than in cPPAR␥ Ϫ/Ϫ and cPPAR␥ ϩ/ϩ mice (data not shown), likely due to the different genetic backgrounds of these mice. To study the effect of pioglitazone on similar levels of cardiac fibrosis in these two mouse models, mPPAR␥ mice were studied after 2 weeks of AngII infusion (Table 2 and Fig.…”