The development of the dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist tesaglitazar as an oral antidiabetic was recently discontinued. Here we present tumor data from a 2-year carcinogenicity study in rats given 0.3, 1, 3, and 10 micromol/kg tesaglitazar is presented with focus on the findings of subcutaneous fibrosarcomas. To investigate the mechanism for induction of fibrosarcomas, replicative DNA synthesis (immunohistochemical detection of BrdU-labeled cells) and expression of PPARgamma (immunohistochemistry and reverse transcription-polymerase chain reaction) in subcutaneous adipose tissues was assessed in rats administered 1 or 10 micromol/kg for 2 weeks or 3 months. Poorly differentiated subcutaneous mesenchymal sarcomas with a predominant spindle cell appearance occurred at the highest dose level of 10 micromol/kg in both sexes, and these tumors were diagnosed as fibrosarcomas. The 10-micromol/kg dose was at or above the maximum tolerated dose and caused considerable cardiovascular mortality. Tesaglitazar stimulated DNA synthesis mainly in subcutaneous interstitial mesenchymal cells. The percentage of BrdU-labeled interstitial cells was increased at 1 and 10 micromol/kg after 2 weeks. The increase in DNA synthesis was still significant at the end of the 12-week treatment at 10 mumol/kg, the dose producing fibrosarcoma. However, at 1 micromol/kg, a dose below the no-observed-effect level for fibrosarcoma, the level of DNA synthesis was similar to control levels at 12 weeks. Immunohistochemical analyses showed no detectable PPARgamma protein in the majority of BrdU-labeled interstitial mesenchymal cells in white and brown fat. This indicates that stimulation of DNA synthesis is not mediated via direct activation of PPARgamma in these cells. The results suggest that the induction of rat fibrosarcoma by tesaglitazar, at exposures 100-fold above the human therapeutic exposure, may involve proliferation of undifferentiated mesenchymal cells in subcutaneous tissues.
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...
Background and purpose:We have evaluated the effects of a peroxisome proliferator-activated receptor (PPAR)a/g agonist on the progression of pre-existing atherosclerotic lesions in APOE*3Leiden.cholesteryl ester transfer protein (E3L.CETP) transgenic mice. Experimental approach: E3L.CETP mice were fed a high-cholesterol diet for 11 weeks to induce atherosclerosis, followed by a low-cholesterol diet for 4 weeks to obtain a lower plasma total cholesterol level of~10 mmol·L -1 . Mice were divided into three groups, which were either killed before (baseline) or after an 8 week treatment period with low-cholesterol diet without (control) or with the PPARa/g agonist tesaglitazar (10 mg·kg -1 ·day -1 ). Atherosclerosis was assessed in the aortic root. Key results: Treatment with tesaglitazar significantly reduced plasma triglycerides, total cholesterol, CETP mass and CETP activity, and increased high-density lipoprotein-cholesterol. At baseline, substantial atherosclerosis had developed. During the 8 week low-cholesterol diet, atherosclerosis progressed in the control group with respect to lesion area and severity, whereas tesaglitazar inhibited lesion progression during this period. Tesaglitazar reduced vessel wall inflammation, as reflected by decreased monocyte adhesion and macrophage area, and modified lesions to a more stabilized phenotype, with increased smooth muscle cell content in the cap and collagen content. Conclusions and implications: Dual PPARa/g agonism with tesaglitazar markedly improved the atherogenic triad by reducing triglycerides and very low-density lipoprotein-cholesterol and increasing high-density lipoprotein-cholesterol and additionally reduced cholesterol-induced vessel wall activation. These actions resulted in complete inhibition of progression and stabilization of pre-existing atherosclerotic lesions in E3L.CETP mice.
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