Comments for:
Abstract
PPARα is a ligand-dependent transcription factor expressed at high levels in the liver. Its activation by the drug gemfibrozil reduces clinical events in humans with established atherosclerosis, but the underlying mechanisms are incompletely defined. To clarify the role of PPARα in vascular disease, we crossed PPARα-null mice with apoE-null mice to determine if the genetic absence of PPARα affects vascular disease in a robust atherosclerosis model. On a high-fat diet, concentrations of atherogenic lipoproteins were higher in PPARα–/–apoE–/– than in PPARα+/+apoE–/– mice, due to increased VLDL production. However, en face atherosclerotic lesion areas at the aortic arch, thoracic aorta, and abdominal aorta were less in PPARα-null animals of both sexes after 6 and 10 weeks of high-fat feeding. Despite gaining as much or more weight than their PPARα+/+apoE–/– littermates, PPARα–/–apoE–/– mice had lower fasting levels of glucose and insulin. PPARα-null animals had greater suppression of endogenous glucose production in hyperinsulinemic clamp experiments, reflecting less insulin resistance in the absence of PPARα. PPARα–/–apoE–/– mice also had lower blood pressures than their PPARα+/+apoE–/– littermates after high-fat feeding. These results suggest that PPARα may participate in the pathogenesis of diet-induced insulin resistance and atherosclerosis.
Authors
Karen Tordjman, Carlos Bernal-Mizrachi, Laura Zemany, Sherry Weng, Chu Feng, Fengjuan Zhang, Teresa C. Leone, Trey Coleman, Daniel P. Kelly, Clay F. Semenkovich
PPARa Deficiency in Bone Marrow-derived Cells Does Not Affect Atherogenesis in APOE*3-Leiden Mice
Submitter: Bart J.M. van Vlijmen | bjm.vanvlijmen@pg.tno.nl
Vascular and Connective Tissue Research, TNO-Prevention and Health / Gaubius Laboratory
Published June 4, 2001
PPARa Deficiency in Bone Marrow-derived Cells Does Not Affect Atherogenesis in APOE*3-Leiden Mice. Els C. de Meijer1, Teake Kooistra1, Theo J.C. van Berkel2, Bart Staels3, Louis M. Havekes1, and Bart J.M. van Vlijmen1 1TNO Prevention and Health, Gaubius Laboratory, P.O. Box 2215, 2301 CE Leiden, The Netherlands; 2Department of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands, 3Institut Pasteur de Lille, Lille, France.
The manuscript by Tordjman and colleagues clearly demonstrates that PPARa deficiency reduces insulin resistance and atherosclerosis in apoE- null mice. In regard to the authors’ discussion whether PPARa deficiency in mice decreases atherosclerosis through systemic or vessel wall effects, we note that bone marrow-derived cells, including macrophages and T-cells are important cell types in the atherosclerotic vessel wall and express PPARa [1]. Thus, effects of PPARa on atherosclerosis as reported by Tordjman and colleagues are possibly related to the absence of PPARa in bone marrow-derived cells, either at the level of the blood or the atherosclerotic vessel wall.
To investigate the role of bone marrow-derived PPARa in the progression of atherosclerosis, atherosclerosis-susceptible APOE*3-Leiden (E3L) transgenic mice were reconstituted with bone marrow from either PPARa deficient mice (PPARa-/- [2]) or their PPARa+/- littermates (controls). Female APOE*3-Leiden (E3L) mice, 8-10 weeks of age, were lethally irradiated (13 Gy) and transplanted with 1.5x107 bone marrow cells derived from either PPARa+/- or PPARa-/- donor mice. Four weeks after bone marrow transplantation the regular chow diet was changed to a high fat/high cholesterol (HFC) diet. After 12 weeks of HFC feeding, the extent of atherosclerosis was quantified at the level of the aortic root (for methodology on bone marrow transplantation and atherosclerosis quantification in APOE*3-Leiden mice see [3]).
After 12 weeks of high fat/high cholesterol feeding, PPARa-/- E3L mice had a normal body weight, and their plasma cholesterol levels, their lipoprotein profiles, and the cellular composition of their blood (the percentage of CD4- and CD8-positive T-cells, B-cells, monocytes and granulocytes) were comparable to PPARa+/- E3L control mice. PCR analysis on genomic DNA from white blood cells of each mouse revealed that 100.0±4.6 and 93.5±2.1% of the white blood cells were of donor genotype for PPARa+/- and PPARa-/- E3L mice, respectively. Semi-quantitative analysis of the atherosclerotic lesions at the level of the aortic root, revealed that both groups had typical III-IV lesions, i.e. mild to moderate plaques with extension of foam cells into the intima, a fibrotic cap and an affected media without loss of architecture. PPARa+/- and PPARa -/- E3L mice had lesion areas of 134.0±57.1*103 mm2 and 140.6±59.9*103 mm2, respectively (P=0.905) and a lesion macrophage area of 88.6±28.7*103 mm2 and 95.5±35.3*103 mm2, respectively (P=0.772).
The identical lesion area and lesion macrophage area in PPARa+/- and PPARa-/- E3L mice indicate that, under the experimental conditions studied here, bone marrow-derived PPARa plays no significant role in atherosclerotic plaque development. Hence, our data suggest that the effects of PPARa on atherosclerosis, as reported by Tordjman and colleagues, are not related to the absence of PPARa in bone marrow-derived cells either at the level of the blood or the atherosclerotic vessel wall.
References
1. Chinetti, G., Gbaguidi, F.G., Griglio, S., Mallat, Z., Antonucci, M., Poulain, P., Chapman, J., Fruchart, J.C., Tedgui, A., Najib-Fruchart, J., Staels, B.. 2000. CLA-1/SR-BI is expressed in atherosclerotic lesion macrophages and regulated by activators of peroxisome proliferator- activated receptors. Circulation. 101:2411-2417.
2. Lee, S.S., Pineau, T., Drago, J., Lee, E.J., Owens, J.W., Kroetz, D.L., Fernandez-Salguero, P.M., Westphal, H., Gonzalez, F.J. 1995. Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol Cell Biol. 15: 3012-3022.
3. van Vlijmen, B.J., Gerritsen, G., Franken, A.L., Boesten, L.S., Kockx, M.M., Gijbels, M.J., Vierboom, M.P., van Eck, M., van de Water, B., van Berkel, T.J., Havekes, L.M. 2001. Macrophage p53 Deficiency Leads to Enhanced Atherosclerosis in APOE*3-Leiden Transgenic Mice. Circ Res.88:780 -786.
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