UC San Diego

Atherosclerosis is a disease of dysregulated inflammation and metabolism. Many nuclear receptors have established roles in regulating metabolism and inflammation through various tissues and cell types, making them attractive therapeutic targets for cardiovascular disease. Thiazolidinediones (TZDs), pharmaceutical ligands for nuclear receptor peroxisome proliferator activated receptor (PPAR[gamma]), are used to improve insulin sensitivity in diabetic patients. Recently their effect on coronary heart disease has been called into question. PPAR[gamma] has been shown to be athero-protective in mice via the macrophage by enhancing cholesterol efflux and suppressing inflammation, but its role in lesion smooth muscle and endothelial cells is unknown. Some reports suggest PPAR[gamma] can suppress oxidation, hypertension and inflammation in the endothelium. Thus, endothelial PPAR[gamma] would be predicted to play a protective role in atherosclerosis. To test this, [PPAR[gamma]-flox, Tie2- cre, LDLr-/- mice were irradiated and reconstituted with wildtype PPAR[gamma] bone marrow to generate an endothelial-specific PPAR[gamma] knockout atherogenic model. Endothelial PPAR[gamma] deficiency resulted in significantly increased lesion area and greater macrophage infiltration. Gene expression of pro-atherosclerotic chemokines and adhesion molecules was increased in primary endothelial cells from PPAR gamma-deficient mice relative to wildtype, both in vivo and with TLR ligand challenge in vitro. In agreement with this support for an anti- inflammatory role, PPAR[gamma] ligand could suppress monocyte adhesion to both human and mouse primary endothelial cells. While PPAR[gamma] ligand did not suppress classic endothelial adhesion molecules such as VCAM and ICAM, it did suppress the membrane-bound chemokine, fractalkine (CX3CL1). This molecule is strongly chemotactic and deficiency of its cognate receptor has been shown to improve atherosclerosis in LDLr-/- mice. Immunohistochemistry, luminex assay and neutralizing antibodies are being employed to determine the contribution of fractalkine to atherosclerosis in the endothelial PPAR[gamma]-deficient model. In an effort to identify additional nuclear receptors as potential targets for cardiovascular disease treatment, primary endothelial gene expression was compared between wildtype mice and LDLr-/- mice fed atherogenic diet. Expression of several nuclear receptors was significantly altered in the atherogenic model and investigation of their function in this context is underway