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Your search keyword '"Heywood, Elizabeth"' showing total 2 results
Start Over Author "Heywood, Elizabeth" Publisher american diabetes association
2 results on '"Heywood, Elizabeth"'

1. PPARα agonists suppress osteopontin expression in macrophages and decrease plasma levels in patients with type 2 diabetes

Author

Nakamachi, Takafumi, Nomiyama, Takashi, Gizard, Florence, Heywood, Elizabeth B., Jones, Karrie L., Zhao, Yue, Fuentes, Lucia, Takebayashi, Kohzo, Aso, Yoshimasa, Staels, Bart, Inukai, Toshihiko, and Bruemmer, Dennis

Subjects
Gene expression -- Research -- Health aspects, Extracellular matrix -- Research -- Health aspects, Plasma cells -- Research -- Health aspects, Diabetics -- Research -- Health aspects, Health
Abstract

Osteopontin (OPN) is a proinflammatory cytokine implicated in the chemoattraction of monocytes and the development of atherosclerosis. Peroxisome proliferator-activated receptor (PPAR)α, a ligand-activated transcription factor with pleiotropic anti-inflammatory effects in macrophages, is the molecular target for flbrates, which are frequently used to treat dyslipidemia in patients with type 2 diabetes at high risk for cardiovascular disease. In the present study, we examined the regulation of OPN by PPARα agonists in macrophages and determined the effect of fibrate treatment on OPN plasma levels in patients with type 2 diabetes. Treatment of human macrophages with the PPARα ligands bezafibrate or WY14643 inhibited OPN expression. PPARα ligands suppressed OPN promoter activity, and an activator protein (AP)-1 consensus site conferred this repression. Overexpression of c-Fos and c-Jun reversed the inhibitory effect of PPARα ligands on OPN transcription, and, in chromatin immunoprecipitation assays, PPARα ligands inhibited c-Fos and phospho-c-Jun binding to the OPN promoter. Moreover, c-Fos and phospho-c-Jun protein expression was inhibited by PPARα agonists, indicating that PPAPα ligands suppress OPN expression through negative cross talk with AP-1-dependent transactivation of the OPN promoter. This inhibitory effect of PPARα ligands on OPN expression was absent in PPARα-deficient macrophages, suggesting a receptor-mediated mechanism of OPN suppression. Finally, treatment of type 2 diabetic patients with bezafibrate significantly decreased OPN plasma levels. These results demonstrate a novel mechanism whereby PPAPα ligands may impact macrophage inflammatory responses and decrease early proinflammatory markers for cardiovascular disease., Osteopontin (OPN) is a secreted extracellular matrix protein and a proinflammatory cytokine that has recently been identified as a key component of cell-mediated immunity (1). OPN is abundantly secreted by [...]

Published
2007

2. The NR4A Orphan Nuclear Receptor NOR1 Regulates Vascular Smooth Muscle Cell Proliferation and Neointima Formation.

Author

Nomiyama, Takashi, Gizard, Florence, Heywood, Elizabeth B., Jones, Karrie, and Bruemmer, Dennis

Subjects
NUCLEAR receptors (Biochemistry), VASCULAR smooth muscle, CELL proliferation, ATHEROSCLEROSIS, PROTEINS
Abstract

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]

Published
2007

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