Peroxisome proliferator-activated receptor a (PPARa) is a transcription factor that plays a key role in regulating the expression of multiple genes involved in lipoprotein, lipid, and carbohydrate metabolism in the liver as well as in other tissues. Multiple clinical studies have demonstrated that patients with cardiovascular disease can greatly benefit by treatment with PPARa activators. These beneficial effects are linked to the well-known hypolipidemic effects of PPARa activators. It has also been hypothesized that PPARa activators exert anti-atherogenic effects by activating PPARa constitutively expressed in various cell types present in atherosclerotic lesions. However, evidence implicating direct anti-atherogenic actions of PPARa agonists on cells of the arterial wall in vivo is currently lacking. Several murine models of atherosclerosis have proven unsuitable to demonstrate a direct effect of PPARa agonists on atherosclerotic lesions. This is mainly due to the fact that, in those animal models, the putative effects of PPARa activation on vascular cells cannot be divorced from the PPARa mediated effects in the liver that cause major alterations on the metabolism of circulating atherogenic lipoproteins which, in turn, affect the development of atherosclerotic lesions. We hypothesize that the effects of PPARa agonists directly on arterial cells can be tested using murine models that fulfill 3 main criteria: a) they are susceptible to the development of atherosclerosis (e.g. mice lacking the genes for the LDL receptor [LDLR-/-] or apolipoprotein E [apoE-/-/]);b) they are normally responsive to PPARa activation in vascular cells, and c) they are unresponsive to PPARa activation selectively in the liver and, therefore, cannot undergo changes in the metabolism of atherogenic lipoproteins in response to treatment with PPARa agonists. The nuclear receptor co-activator PBP (PPAR- Binding Protein) is essential for PPARa - regulated gene expression and its absence in hepatocytes causes an almost complete abrogation of ligand-induced PPARa activation. Thus, mice with targeted deletion of PBP in liver parenchymal cells (lpcPBP-/-) can be used as surrogates for mice with targeted deletion of PPARa in liver parenchymal cells. The objectives of this proposal are: a) to use the already available lpcPBP-/- mice to generate LDLR-/-/lpcPBP-/- and apoE-/-/lpcPBP-/- mice that are selectively unresponsive to PPARa activation in the liver, and b) to treat these animals with low- and high-potency PPARa agonists and investigate the effects of their actions on arterial cells on the development and regression of atherosclerotic lesions. Atherosclerosis and its complications are a major public health problem, accounting for over half the annual mortality in the United States. In this application we propose to use mouse models of this disease to elucidate the mechanisms whereby certain drugs, by acting directly on blood vessels, can prevent the development, or cause the regression of atherosclerotic lesions.
