Our data indicate that TNFalpha stimulates the formation of lesions towards an advanced phenotype, with more lesion necrosis and a lower incidence of apoptosis.

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...

These data demonstrate that advanced murine plaques are sensitive to Fas/FasL-induced apoptosis, which may indicate that stimulation of this pathway could result in plaque remodelling towards a more vulnerable phenotype.

No abstract

The cellular composition of an atherosclerotic lesion is determined by cell infiltration, proliferation, and apoptosis. The tumor suppressor gene retinoblastoma (Rb) has been shown to regulate both cell proliferation and cell death in many cell types. To study the role of macrophage Rb in the development of atherosclerosis, we used apoE-deficient mice with a macrophage-restricted deletion of Rb (Rb(del) mice) and control littermates (Rb(fl) mice). After 12 wk feeding a cholesterol-rich diet, the Rb(del) mice showed a 51% increase in atherosclerotic lesion area with a 39% increase in the relative number of advanced lesions. Atherosclerotic lesions showed a 13% decrease in relative macrophage area and a 46% increase in relative smooth muscle cell area, reflecting the more advanced state of the lesions. The increase in atherosclerosis was independent of in vitro macrophage modified lipoprotein uptake or cytokine production. Whereas macrophage-restricted Rb deletion did not affect lesional macrophage apoptosis, a clear 2.6-fold increase in lesional macrophage proliferation was observed. These studies demonstrate that macrophage Rb is a suppressing factor in the progression of atherosclerosis by reducing macrophage proliferation.