Abstract 1679: Nuclear Receptor Nur77 and 6-Mercaptopurine Protect against Atherosclerosis
Nur77 is an orphan nuclear receptor of the NR4A subfamily, which also comprises Nurr1 (NR4A2) and NOR-1 (NR4A3). We were the first to describe the expression of Nur77 in human atherosclerotic lesions both in macrophages and in activated, intimal smooth muscle cells. Here we demonstrate that Nur77 is expressed in human instent restenotic lesions that were obtained through coronary atherectomy. The generation of transgenic mice that overexpress Nur77 specifically in arterial smooth muscle cells allowed us to study the function of Nur77 in the injured vessel wall in vivo. Nur77 inhibits the formation of smooth muscle cell-rich lesions in the carotid artery ligation model, as well as in the femoral artery loosely-fitting cuff model. Both models relate to human (instent) restenotic lesions that are also composed predominantly of smooth muscle cells. Recently, it has been shown that 6-mercaptopurine (6-MP) enhances the activity of Nur77 and we demonstrated in a drug-eluting cuff mouse model that 6-MP reduces lesion formation in a Nur77-dependent way. In atherosclerosis, monocytes and macrophages are important in initiation and progression of the disease. We demonstrated that Nur77 downregulates the expression of inflammatory cytokines and chemokines and inhibits the uptake of oxidized LDL particles in macrophages. To extend our knowledge on Nur77 function in atherosclerosis we cross-bred our Nur77-transgenic mice with ApoE-/- mice and studied high-fat/cholesterol diet induced lesion formation in the aortic sinus. Nur77 overex-pression in smooth muscle cells reduces lesion formation in response to this diet. In conclusion, our data demonstrate that Nur77 and its agonist 6-MP inhibit vascular lesion formation and atherosclerosis.
Supported by The Netherlands Heart Foundation grants M93.007 and 2003B199.