Activation of the nuclear hormone receptor peroxisome proliferatoractivated receptor ␦ (PPAR␦) has been shown to improve insulin resistance, adiposity, and plasma HDL levels. However, its antiatherogenic role remains controversial. Here we report atheroprotective effects of PPAR␦ activation in a model of angiotensin II (AngII)-accelerated atherosclerosis, characterized by increased vascular inflammation related to repression of an antiinflammatory corepressor, B cell lymphoma-6 (Bcl-6), and the regulators of G protein-coupled signaling (RGS) proteins RGS4 and RGS5. In this model, administration of the PPAR␦ agonist GW0742 (1 or 10 mg/kg) substantially attenuated AngII-accelerated atherosclerosis without altering blood pressure and increased vascular expression of Bcl-6, RGS4, and RGS5, which was associated with suppression of inflammatory and atherogenic gene expression in the artery. In vitro studies demonstrated similar changes in AngII-treated macrophages: PPAR␦ activation increased both total and free Bcl-6 levels and inhibited AngII activation of MAP kinases, p38, and ERK1/2. These studies uncover crucial proinflammatory mechanisms of AngII and highlight actions of PPAR␦ activation to inhibit AngII signaling, which is atheroprotective.peroxisome proliferator-activated receptor ␦ ͉ vascular inflammation ͉ macrophage

Abstract-The liver X receptors ␣ and ␤ (LXR␣ and LXR␤) are important regulators of cholesterol homeostasis in liver and macrophages. Synthetic LXR ligands prevent the development of atherosclerosis in murine models; however, the potential functional relevance of LXRs in vascular smooth muscle cells (VSMCs) has not been investigated. In the present study, we demonstrate that LXRs are expressed and functional in primary human coronary artery VSMCs (CASMCs). LXR ligands inhibited mitogen-induced VSMC proliferation and G 1 3 S phase progression of the cell cycle. Inhibition of G 1 exit by LXR ligands was accompanied by a dose-dependent inhibition of retinoblastoma protein (Rb) phosphorylation, which functions as the key switch for G 1 3 S cell cycle progression. LXR ligands suppressed mitogen-induced degradation of the cyclin-dependent kinase inhibitor p27 Kip1 , attenuated cyclin D1 and cyclin A expression, and inhibited the expression of S phase-regulatory minichromosome maintenance protein 6. Stabilization of p27 kip1 by LXR ligands was mediated by supressing the transcriptional activation of the S phase kinase-associated protein 2 (Skp2), an F-box protein that targets p27Kip1 for degradation. Inhibition of Rb phosphorylation and G 1 3 S cell cycle progression by LXR ligands was reversed in VSMCs overexpressing Skp2, indicating that Skp2 as an upstream regulator of p27Kip1 degradation plays a central role in LXR ligand-mediated inhibition of VSMC proliferation. Furthermore, adenovirus-mediated overexpression of the S phase transcription factor E2F, which is released after Rb phosphorylation, reversed the inhibitory effect of LXR ligands on VSMC proliferation and S phase gene expression, suggesting that the primary mechanisms by which LXR ligands inhibit VSMC proliferation occur upstream of Rb phosphorylation. Finally, neointima formation in a model of rat carotid artery balloon injury was significantly attenuated after treatment with the LXR ligand T1317 compared with vehicle-treated animals. These data demonstrate that LXR ligands inhibit VSMC proliferation and neointima formation after balloon injury and suggest that LXR ligands may constitute a novel therapy for proliferative vascular diseases. The full text of this article is available online at http://circres.ahajournals.org. (Circ Res. 2004;95:e110-e123.) Key Words: vascular smooth muscle cell Ⅲ liver X receptor Ⅲ arterial injury C ardiovascular disease is the leading cause of mortality in industrialized nations, accounting for nearly 50% of all deaths. 1 Vascular smooth muscle cell (VSMC) activation, migration, and proliferation in response to injury play not only a decisive role for development of atherosclerosis but are also the primary pathophysiologic mechanism resulting in the failure of procedures used to treat occlusive proliferative atherosclerotic diseases, such as postangioplasty restenosis, transplant vasculopathy, and vein bypass graft failure. 2,3 Although much effort has been devoted to targeting VSMC activation and proliferation, effective t...

Abstract-Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. The 3 PPAR isotypes, PPAR-␣, PPAR-␥, and PPAR-␦, play a key role in the regulation of lipid and glucose metabolism. Obesity and the interrelated disorders of the metabolic syndrome have become a major worldwide health problem. In this review, we summarize the critical role of PPARs in regulating inflammation, lipoprotein metabolism, and glucose homeostasis and their potential implications for the treatment of obesity, diabetes, and atherosclerosis. Key Words: PPARs Ⅲ atherosclerosis Ⅲ obesity Ⅲ diabetes T ype 2 diabetes is a complex metabolic disorder that affects between 6% and 20% of the population in Western industrialized societies. Around the globe, the prevalence of type 2 diabetes is expected to increase exponentially, especially among the young. 1 Type 2 diabetes is characterized by hyperglycemia, insulin resistance, and progressive loss of ␤-cell function throughout the course of the disease and is associated with dyslipidemia, hypertension, and obesity (components of the metabolic syndrome). 2 Both type 1 and type 2 diabetes are considered a coronary artery disease (CAD) risk equivalent. 3 However, CAD often precedes the onset of diabetes, because 50% of patients with new onset type 2 diabetes already have a CAD diagnosis.Components of the metabolic syndrome-insulin resistance, hypertension, low high-density lipoprotein (HDL), and hypertriglyceridemia-are themselves CAD risk factors, whereas hyperglycemia additionally contributes to vascular damage. Whether hyperinsulinemia and insulin resistance directly contribute to vascular damage is controversial and under active investigation. 4 Although type 1 and 2 diabetes are associated with increased atherosclerosis, the pathogenesis of CAD in diabetes is multifactorial. Changes in metabolic factors, increased oxidative stress and glycoxidation, endothelial dysfunction, inflammation, and the prothrombotic state, observed in diabetics play a role in cardiovascular complications of diabetes. 5 Initially, type 2 diabetes was referred to as disorder of carbohydrate metabolism. For the past decade, it was considered a disorder of fatty acid metabolism, because free fatty acids (FFAs) circulate in high levels in obesity and promote insulin resistance and hepatic glucose production. 6 Recently, increasing evidence indicates that abnormalities in adipokine secretion from fat and in mitochondrial metabolism play a central role in the pathogenesis of this disease. 7,8 Insulin resistance, defined as a defect in the ability of insulin to drive glucose into its major target tissue, skeletal muscle, 9 is a key factor in the pathogenesis of type 2 diabetes and a cofactor in the development of dyslipidemia, hypertension, and atherosclerosis. 10 Insulin resistance is present in Ͼ90% of people with type 2 diabetes and predates the development of hyperglycemia by many years. 11 In the early states, insulin resistance is ...

SUMMARYBehavior and physiology are regulated by both environment and social context. A central goal in the study of the social control of behavior is to determine the underlying physiological, cellular and molecular mechanisms in the brain. The African cichlid fish Astatotilapia burtoni has long been used as a model system to study how social interactions regulate neural and behavioral plasticity. In this species, males are either socially dominant and reproductively active or subordinate and reproductively suppressed. This phenotypic difference is reversible. Using an integrative approach that combines quantitative behavioral measurements, functional genomics and bioinformatic analyses, we examine neural gene expression in dominant and subordinate males as well as in brooding females. We confirm the role of numerous candidate genes that are part of neuroendocrine pathways and show that specific co-regulated gene sets (modules), as well as specific functional gene ontology categories, are significantly associated with either dominance or reproductive state. Finally, even though the dominant and subordinate phenotypes are robustly defined, we find a surprisingly high degree of individual variation in the transcript levels of the very genes that are differentially regulated between these phenotypes. The results of the present study demonstrate the molecular complexity in the brain underlying social behavior, identify novel targets for future studies, validate many candidate genes and exploit individual variation in order to gain biological insights. Supplementary material available online at