Dual PPARα/γ Agonist Tesaglitazar Reduces Atherosclerosis in Insulin-Resistant and Hypercholesterolemic ApoE*3Leiden Mice

Abstract

Objective-We investigated whether the dual PPAR␣/␥ agonist tesaglitazar has anti-atherogenic effects in ApoE*3Leiden mice with reduced insulin sensitivity. Methods and Results-ApoE*3Leiden transgenic mice were fed a high-fat (HF) insulin-resistance-inducing diet. One group received a high-cholesterol (HC) supplement (1% wt/wt; HC group). A second group received the same HC supplement along with tesaglitazar (T) 0.5 mol/kg diet (T group). A third (control) group received a low-cholesterol (LC) supplement (0.1% wt/wt; LC group). Tesaglitazar decreased plasma cholesterol by 20% compared with the HC group; cholesterol levels were similar in the T and LC groups. Compared with the HC group, tesaglitazar caused a 92% reduction in atherosclerosis, whereas a 56% reduction was seen in the cholesterol-matched LC group. Furthermore, tesaglitazar treatment significantly reduced lesion number beyond that expected from cholesterol lowering and induced a shift to less severe lesions. Concomitantly, tesaglitazar reduced macrophage-rich and collagen areas. In addition, tesaglitazar reduced inflammatory markers, including plasma SAA levels, the number of adhering monocytes, and nuclear factor B-activity in the vessel wall. Key Words: atherosclerosis Ⅲ cholesterol Ⅲ inflammation Ⅲ inhibitors A gonists of the peroxisome proliferator-activated receptor (PPAR)␣ have positive effects on lipid metabolism both in animal models and in clinical practice. [1][2][3] Agonists of PPAR␥, the thiazolidinediones rosiglitazone and pioglitazone, improve insulin resistance in type 2 diabetes, and pioglitazone improves the dyslipidemia associated with insulin resistance. 4 -6 In addition to these effects, both PPAR␣ and PPAR␥ agonists have anti-inflammatory properties 7,8 that can provide additional cardiovascular benefit. 9 PPAR␣ and PPAR␥ agonists could reduce atherosclerosis by improving the dyslipidemia of insulin resistance and by modulating the low-level chronic inflammatory response induced by this disease. Systemically, they ameliorate the atherogenic lipid profile by reducing plasma free fatty acids and triglycerides, and increasing high-density lipoprotein (HDL) cholesterol levels. 10 At the cellular level, PPAR agonists act on most cell types involved in atherosclerosis, including endothelial cells, smooth muscle cells (SMCs), macrophages, and lymphocytes, reducing their involvement in the tissue response associated with plaque development. These agonists reduce levels of plasma proteins such as C-reactive protein (CRP), tumor necrosis factor (TNF) ␣, and interferon ␥ 11 ; inhibit IL-2 and TNF␣ secretion by monocytes 12 ; and reduce IL-1-induced secretion of IL-6 via nuclear factor (NF) B signaling pathways in SMCs. 13,14 PPAR agonists have a number of other actions that positively modulate vascular effects. In the endothelium, for example, they inhibit production of the vasoconstrictor endothelin-1 15,16 and inhibit cytokine-induced expression of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion...

Mouse Models for Atherosclerosis and Pharmaceutical Modifiers

“…123 Another PPAR␣/␥ coagonist, tesaglitazar, reduced atherosclerosis by 92% in E3L mice. 124 In line with the observations of Zuckerman, tesaglitazar exerted antiatherosclerotic effects beyond plasma cholesterol-lowering, including antiinflammatory, NFB-reducing vascular effects. Chira et al, 125 using female LDLr Ϫ/Ϫ mice, also found that tesaglitazar reduced atherosclerosis via lipid-independent mechanisms, probably at least in part by direct actions on the vessels.…”

Direct antiatherosclerotic effects of PPAR agonists

“…For example, tesaglitazar was associated with a 92% reduction in aortic atherosclerosis in apoEÃLeiden mice and LDL-receptor knockout mice fed a high-fat diet [65,66 ]. In contrast, we found that treatment with the dual PPARa/g agonist, compound 3q was associated with an increase in atherosclerosis in male apoE knockout mice [67 ].…”

Aspirin Inhibits MMP-2 and MMP-9 Expressions and Activities through Upregulation of PPARα/γ and TIMP Gene Expressions in ox-LDL-Stimulated Macrophages Derived from Human Monocytes

“…A previous study found that MMP-9 secretion was blocked not only by rosiglitazone, a PPAR ␥ agonist, but also by fenofibrate, a PPAR ␣ agonist [11] . Another recent study has further demonstrated that tesaglitazar (a dual PPAR ␣ / ␥ agonist) had an anti-atherosclerotic effect in the mouse model, possibly due to a combination of altered lipoprotein profiles and anti-inflammatory effect [21] . It has also been reported that activations of PPAR ␣ and PPAR ␥ might inhibit the expression of pro-inflammatory cytokines in vascular cells, potentially contributing to their anti-atherosclerotic action [22,23] .…”