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Background: The NR4A3 orphan nuclear hormone receptor, NOR1, functions as a constitutively active transcription factor to regulate inflammation, proliferation, and cell survival during pathological vascular remodeling. Inflammatory processes represent key mechanisms leading to abdominal aortic aneurysm (AAA) formation. However, a role of NOR1 in AAA formation has not been investigated previously.Methods: Inflammatory gene expression was analyzed in bone marrow-derived macrophages isolated from NOR1-deficient mice. Low-density lipoprotein receptor-deficient (LDLr-/-) mice were irradiated and reconstituted with hematopoietic stem cells obtained from NOR1-/- or wild-type littermate mice. Animals were infused with angiotensin II and fed a diet enriched in saturated fat to induce AAA formation. Quantification of AAA formation was performed by ultrasound and ex vivo measurements.Results: Among 184 inflammatory genes that were analyzed, 36 genes were differentially regulated in LPS-treated NOR1-deficient macrophages. Albeit this difference in gene regulation, NOR1-deficiency in hematopoietic stem cells did not affect development of AAA formation in bone marrow-derived stem cell transplanted LDLr-deficient mice.Conclusion: NOR1 deletion induced differential inflammatory gene transcription in macrophages but did not influence AAA formation in mice. [ABSTRACT FROM AUTHOR]

The NR4A orphan nuclear receptors function as early response genes to numerous stimuli. Our laboratory has previously demonstrated that overexpression of NR4A3 (NOR-1, MINOR) in 3T3-L1 adipocytes enhances insulinstimulated glucose uptake. To assess the in vivo effect of NR4A3 on adipocytes, we generated transgenic mice with NR4A3 overexpression driven by the adipocyte fatty acid-binding protein (AP2) promoter (AP2-NR4A3 mice). We hypothesized that AP2-NR4A3 mice would display enhanced glucose tolerance and insulin sensitivity. However, AP2-NR4A3 mice exhibit metabolic impairment, including increased fasting glucose and insulin, impaired glucose tolerance, insulin resistance, decreased serum free fatty acids, and increased low-density lipoprotein-cholesterol. AP2-NR4A3 mice also display a significant reduction in serum epinephrine due to increased expression of catecholamine-catabolizing enzymes in adipose tissue, including monoamine oxidase-A. Furthermore, enhanced expression of monoamine oxidase-A is due to direct transcriptional activation by NR4A3. Finally, AP2-NR4A3 mice display cardiac and behavioral alterations consistent with chronically low circulating epinephrine levels. In conclusion, overexpression of NR4A3 in adipocytes produces a complex phenotype characterized by impaired glucose metabolism and low serum catecholamines due to enhanced degradation by adipose tissue. [ABSTRACT FROM AUTHOR]

Telomerase reverse transcriptase (TERT) maintains telomeres and is rate limiting for replicative life span. While most somatic tissues silence TERT transcription resulting in telomere shortening, cells derived from cancer or cardiovascular diseases express TERT and activate telomerase. In the present study, we demonstrate that histone deacetylase (HDAC) inhibition induces TERT transcription and promoter activation. At the protein level in contrast, HDAC inhibition decreases TERT protein abundance through enhanced degradation, which decreases telomerase activity and induces senescence. Finally, we demonstrate that HDAC inhibition decreases TERT expression during vascular remodeling in vivo. These data illustrate a differential regulation of TERT transcription and protein stability by HDAC inhibition and suggest that TERT may constitute an important target for the anti-proliferative efficacy of HDAC inhibitors. J. Cell. Physiol. 231: 1276-1282, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The nuclear receptor NOR1 is an immediate‐early response gene implicated in the transcriptional control of proliferation. Since the expression level of NOR1 is rapidly induced through cAMP response element binding (CREB) protein‐dependent promoter activation, we investigated the contribution of histone acetylation to this transient induction. We demonstrate that NOR1 transcription is induced by histone deacetylase (HDAC) inhibition and by depletion of HDAC1 and HDAC3. HDAC inhibition activated the NOR1 promoter, increased histone acetylation and augmented the recruitment of phosphorylated CREB to the promoter. Furthermore, HDAC inhibition increased Ser133 phosphorylation of CREB and augmented NOR1 protein stability. These data outline previously unrecognized mechanisms of NOR1 regulation and illustrate a key role for histone acetylation in the rapid induction of NOR1.NOR1 transcription is induced by histone deacetylase inhibition through chromatin modification. HDAC inhibition increases CREB phosphorylation and its recruitment to CRE consensus motifs within the NOR1 promoter. HDAC inhibition augments NOR1 protein stability. [ABSTRACT FROM AUTHOR]

The NR4A orphan nuclear receptor NOR1 functions as a constitutively active transcription factor regulating cellular inflammation and proliferation. In this study, we used bone marrow transplantation to determine the selective contribution of NOR1 expression in hematopoietic stem cells to the development of atherosclerosis. Reconstitution of lethally irradiated apoE−/− mice with NOR1-deficient hematopoietic stem cells accelerated atherosclerosis formation and macrophage recruitment following feeding a diet enriched in saturated fat. NOR1 deficiency in hematopoietic stem cells induced splenomegaly and monocytosis, specifically the abundance of inflammatory Ly6C+ monocytes. Bone marrow transplantation studies further confirmed that NOR1 suppresses the proliferation of macrophage and dendritic progenitor (MDP) cells. Expression analysis identified RUNX1, a critical regulator of hematopoietic stem cell expansion, as a target gene suppressed by NOR1 in MDP cells. Finally, in addition to inducing Ly6C+ monocytosis, NOR1 deletion increased the replicative rate of lesional macrophages and induced local foam cell formation within the atherosclerotic plaque. Collectively, our studies demonstrate that NOR1 deletion in hematopoietic stem cells accelerates atherosclerosis formation by promoting myelopoiesis in the stem cell compartment and by inducing local proatherogenic activities in the macrophage, including lesional macrophage proliferation and foam cell formation. S tem C ells 2014;32:2419-2429 [ABSTRACT FROM AUTHOR]

Excessive accumulation of reactive oxygen species (ROS) in adipose tissue has been implicated in the development of insulin resistance and type 2 diabetes. However, emerging evidence suggests a physiologic role of ROS in cellular signaling and insulin sensitivity. In this study, we demonstrate that pharmacologic depletion of the antioxidant glutathione in mice prevents diet-induced obesity, increases energy expenditure and locomotor activity, and enhances insulin sensitivity. These observations support a beneficial role of ROS in glucose homeostasis and warrant further research to define the regulation of metabolism and energy balance by ROS. [ABSTRACT FROM AUTHOR]

Aging constitutes a major independent risk factor for the development of type 2 diabetes and is accompanied by insulin resistance and adipose tissue dysfunction. One of the most important factors implicitly linked to aging and age-related chronic diseases is the accumulation of oxidative stress. However, the effect of increased oxidative stress on adipose tissue biology remains elusive. In this study, we demonstrate that aging in mice results in a loss of fat mass and the accumulation of oxidative stress in adipose tissue. In vitro, increased oxidative stress through glutathione depletion inhibits preadipocyte differentiation. This inhibition of adipogenesis is at least in part the result of reduced cell proliferation and an inhibition of G1→S-phase transition during the initial mitotic clonal expansion of the adipocyte differentiation process. While phosphorylation of the retinoblastoma protein (Rb) by cyclin/cdk complexes remains unaffected, oxidative stress decreases the expression of S-phase genes downstream of Rb. This silencing of S phase gene expression by increased oxidative stress is mediated through a transcriptional mechanism involving the inhibition of E2F recruitment and transactivation of its target promoters. Collectively, these data demonstrate a previously unrecognized role of oxidative stress in the regulation of adipogenesis which may contribute to age-associated adipose tissue dysfunction. [ABSTRACT FROM AUTHOR]

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 fibrates, 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 PPAPα 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 PPAPα 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 PPARα 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 PPARα ligands may impact macrophage inflammatory responses and decrease early proinflammatory markers for cardiovascular disease. Diabetes 56:1662-1670, 2007 [ABSTRACT FROM AUTHOR]

Grandparents raising grandchildren in the absence of the grandchildren's biological parents are responsible for the emotional, social, and financial well-being of 1.35 million children in the United States (Woodworth, 1996). These custodial grandparents, while providing their grandchildren with a sense of continuity, stability, and security (O'Reilly & Morrison, 1993), often do so at serious emotional, physical, and financial cost to themselves (Pinson-Millburn, Fabian, Schlossberg, & Pyle, 1996). The prevalence and population of grandparents raising grandchildren and identified problem-- and treatment--focus areas for them are described through a review of the literature. Research into specific treatment modalities for these family constellations is significantly lacking. Narrative family therapy is suggested as a viable clinical intervention for this group. [ABSTRACT FROM AUTHOR]

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]