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Nuclear hormone receptors comprise a large superfamily of ligand-activated transcription factors and have emerged as key regulators of glucose metabolism and inflammation in diabetes and cardiovascular diseases. The neuronderived orphan receptor-1 (NOR1) belongs to the ligand-independent NR4A receptor subfamily which has previously been characterized as important transcriptional regulator of hepatic gluconeogenesis and inflammation. We have recently demonstrated NOR1 expression in vascular smooth muscle cells (SMC) of atherosclerotic lesions and outlined a key role for NOR1 to regulate SMC proliferation in vitro. In the present study, we demonstrate that SMC isolated from NOR1-deficient mice exhibit decreased cell proliferation due to a G2/M arrest of the cell cycle. NOR1 -deficiency results in diminished phosphorylation of the retinoblastoma protein, cyclin D1 and D2 expression and mitogen-induced degradation of the cyclin-dependent kinase inhibitor p27. Using microarray technology we further characterize Skp2, Cul1, and Nedd8, key proteins of the ubiquitin ligase complex required for degradation of p27 through the proteasome pathway, as NOR1 target genes. Finally, using a model of guide-wire induced arterial injury we observed decreased neointima formation in NOR1-deficient mice. These experiments demonstrate that NOR1 functions as a key. transcriptional regulator of SMC proliferation and neointima formation by inducing the expression of genes required for the ubiquitination and degradation of p27. Therefore, NOR1 expression may provide an important link between diabetes and cardiovascular disease. [ABSTRACT FROM AUTHOR]