The protein p27(Kip1) regulates cell cycle progression in mammals by inhibiting the activity of cyclin-dependent kinases (CDKs). Here we show that p27(Kip1) progressively accumulates in the nucleus of pancreatic beta cells in mice that lack either insulin receptor substrate 2 (Irs2(-/-)) or the long form of the leptin receptor (Lepr(-/-) or db/db). Deletion of the gene encoding p27(Kip1) (Cdkn1b) ameliorated hyperglycemia in these animal models of type 2 diabetes mellitus by increasing islet mass and maintaining compensatory hyperinsulinemia, effects that were attributable predominantly to stimulation of pancreatic beta-cell proliferation. Thus, p27(Kip1) contributes to beta-cell failure during the development of type 2 diabetes in Irs2(-/-) and Lepr(-/-) mice and represents a potential new target for the treatment of this condition.

As atherosclerosis progressed, the expression of p22phox increased through the vessel wall. p22phox might participate in the pathogenesis and pathophysiology of atherosclerotic coronary disease.

OBJECTIVE-Adipose tissue serves as an integrator of various physiological pathways, energy balance, and glucose homeostasis. Forkhead box-containing protein O subfamily (FoxO) 1 mediates insulin action at the transcriptional level. However, physiological roles of FoxO1 in adipose tissue remain unclear.RESEARCH DESIGN AND METHODS-In the present study, we generated adipose tissue-specific FoxO1 transgenic mice (adipocyte protein 2 [aP 2 ]-FLAG-⌬256) using an aP 2 promoter/ enhancer and a mutant FoxO1 (FLAG⌬256) in which the carboxyl terminal transactivation domain was deleted. Using these mice, we analyzed the effects of the overexpression of FLAG⌬256 on glucose metabolism and energy homeostasis. RESULTS-The aP 2 -FLAG-⌬256 mice showed improved glucose tolerance and insulin sensitivity accompanied with smallersized adipocytes and increased adiponectin (adipoq) and Glut 4 (Slc2a4) and decreased tumor necrosis factor ␣ (Tnf) and chemokine (C-C motif) receptor 2 (Ccr2) gene expression levels in white adipose tissue (WAT) under a high-fat diet. Furthermore, the aP 2 -FLAG-⌬256 mice had increased oxygen consumption accompanied with increased expression of peroxisome proliferator-activated receptor ␥ coactivator (PGC)-1␣ protein and uncoupling protein (UCP)-1 (Ucp1), UCP-2 (Ucp2), and ␤3-AR (Adrb3) in brown adipose tissue (BAT). Overexpression of FLAG⌬256 in T37i cells, which are derived from the hibernoma of SV40 large T antigen transgenic mice, increased expression of PGC-1␣ protein and Ucp1. Furthermore, knockdown of endogenous FoxO1 in T37i cells increased Pgc1␣ (Ppargc1a), Pgc1␤ (Ppargc1b), Ucp1, and Adrb3 gene expression.CONCLUSIONS-These data suggest that FoxO1 modulates energy homeostasis in WAT and BAT through regulation of adipocyte size and adipose tissue-specific gene expression in response to excessive calorie intake. Diabetes 57:563-576, 2008

Objective-C-reactive protein (CRP), a predictor of cardiovascular events, localizes in atherosclerotic arteries and exerts proinflammatory effects on vascular cells. Reactive oxygen species (ROS) have been implicated in atherogenesis and plaque instability. Methods and Results-Expressional pattern of CRP in directional coronary atherectomy specimens from 39 patients was examined. Characteristics of histological plaque instability and higher levels of serum CRP and fibrinogen were associated with the CRP immunoreactivity. In situ hybridization revealed the presence of CRP mRNA in coronary vasculature. Furthermore, the expression of CRP mRNA and protein was detected in cultured human coronary artery smooth muscle cells (CASMCs) by reverse transcriptase-polymerase chain reaction and Western blotting. In addition, CRP was frequently colocalized with p22 phox , an essential component of NADH/NADPH oxidase, which is an important source of ROS in vasculature. Moreover, the incubation of cultured CASMCs with CRP resulted in the enhanced p22 phox protein expression and in the generation of intracellular ROS. Conclusions-The expression of CRP in coronary arteries was associated with histological and clinical features of vulnerable plaque, and it had a prooxidative effect on cultured CASMCs, suggesting that it might play a crucial role in plaque instability and in the pathogenesis of acute coronary syndrome via its prooxidative effect. Key Words: C-reactive protein Ⅲ inflammation Ⅲ oxidative stress Ⅲ free radicals Ⅲ coronary artery diseases A therosclerosis is a chronic inflammatory disease. This concept is supported by recent findings where systemic inflammatory markers such as C-reactive protein (CRP) and fibrinogen are regarded as strong predictors of cardiovascular complications in various clinical settings. [1][2][3] Fibrinogen, a key coagulation factor, is considered to contribute atherogenesis by promoting platelet aggregation, fibrin formation, and plasma viscosity. 4 However, the role of CRP in the pathogenesis of atherosclerotic vascular diseases remains unknown. Recent histological investigations have demonstrated that CRP is present in the human arterial intima at atherosclerotic lesions and is frequently colocalized with the terminal complement complex. 5 Moreover, in vitro studies have shown that the stimulation of human endothelial cells with CRP induces the expression of adhesion molecules and monocyte chemoattractant protein-1 (MCP-1). 6,7 These data suggest that CRP might have direct proinflammatory effects on vascular cells which might, in part, explain the involvement of inflammation in atherogenesis.Reactive oxygen species (ROS) have been implicated in the pathogenesis of a variety of vascular diseases, including atherosclerosis. To date, many types of cells in vasculature have been shown to generate ROS. There are various potential sources that generate ROS in vascular cells: the mitochondrial electron transport chain, cyclooxygenase, lipoxygenase, xanthine oxidase, and NADH/NADPH oxidase. 8,9 Recent ...

Objective-NADH/NADPH oxidase is an important source of reactive oxygen species (ROS) in the vasculature. Recently, we demonstrated that p22 phox , an essential component of this oxidase, was expressed in human coronary arteries and that its expression was enhanced with the progression of atherosclerosis. The present study was undertaken to investigate its functional importance in the pathogenesis of coronary artery disease. For this aim, the expression of p22 phox , the distribution of oxidized low density lipoprotein (LDL), and the generation of ROS in directional coronary atherectomy (DCA) specimens were examined. Methods and Results-DCA specimens were obtained from patients with stable or unstable angina pectoris. The distribution of p22 phox and of oxidized LDL was examined by immunohistochemistry. The generation of superoxide in DCA specimens was assessed by the dihydroethidium method and lucigenin-enhanced chemiluminescence. ROS were closely associated with the distribution of p22 phox and oxidized LDL. Not only inflammatory cells but also smooth muscle cells and fibroblasts generated ROS. There was a correlation between ROS and the expression of p22 phox or oxidized LDL. The generation of ROS was significantly higher in unstable angina pectoris compared with stable angina pectoris. Conclusions-ROS generated by p22phox -based NADH/NADPH oxidase likely mediate the oxidative modification of LDL and might play a major role in pathogenesis of atherosclerotic coronary artery disease. (Arterioscler Thromb Vasc Biol.

Background: Liver dysfunction in adult hypopituitary patients with GH deficiency (GHD) has been reported and an increased prevalence of nonalcoholic fatty liver disease (NAFLD) has been suggested. Objective: The objective of the present study was to elucidate the pathophysiology of the liver in adult hypopituitary patients with GHD. Patients and methods: We recruited 69 consecutive Japanese adult hypopituitary patients with GHD and examined the prevalence of NAFLD by ultrasonography and nonalcoholic steatohepatitis (NASH) by liver biopsy. Patients had been given routine replacement therapy except for GH. We compared these patients with healthy age-, gender-, and BMI-matched controls. We further analyzed the effect of GH replacement therapy on liver function, inflammation and fibrotic markers, and histological changes. Results: The prevalence of NAFLD in hypopituitary patients with GHD was significantly higher than in controls (77 vs 12%, P!0.001). Of 16 patients assessed by liver biopsy, 14 (21%) patients were diagnosed with NASH. GH replacement therapy significantly reduced serum liver enzyme concentrations in the patients and improved the histological changes in the liver concomitant with reduction in fibrotic marker concentrations in patients with NASH. Conclusions: Adult hypopituitary patients with GHD demonstrated a high NAFLD prevalence. The effect of GH replacement therapy suggests that the NAFLD is predominantly attributable to GHD.

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SHPS-1 is a receptor-type glycoprotein that binds and activates the protein-tyrosine phosphatases SHP-1 and SHP-2, and thereby negatively modulates intracellular signaling initiated by various cell surface receptors coupled to tyrosine kinases. SHPS-1 also regulates intercellular communication in the neural and immune systems through its association with CD47 (integrin-associated protein) on adjacent cells. Furthermore, recent studies with fibroblasts derived from mice expressing an SHPS-1 mutant that lacks most of the cytoplasmic region suggested that the intact protein contributes to cytoskeletal function. Mice homozygous for this SHPS-1 mutation have now been shown to manifest thrombocytopenia. These animals did not exhibit a defect in megakaryocytopoiesis or in platelet production. However, platelets were cleared from the bloodstream more rapidly in the mutant mice than in wild-type animals. Furthermore, peritoneal macrophages from the mutant mice phagocytosed red blood cells more effectively than did those from wild-type mice; in addition, they exhibited an increase both in the rate of cell spreading and in the formation of filopodia-like structures at the cell periphery. These results indicate that SHPS-1 both contributes to the survival of circulating platelets and down-regulates the macrophage phagocytic response.SHPS-1 is a transmembrane glycoprotein that is abundant in neural and myeloid tissues (1-6). This molecule is also known as SIRP␣1 (7), BIT (8), MFR (9), and p84 neural adhesion molecule (10). The cytoplasmic region of SHPS-1 contains two immunoreceptor tyrosine-based inhibitory motifs, which recruit and activate the Src homology 2 domain-containing protein-tyrosine phosphatases SHP-1 and SHP-2 in a phosphorylation-dependent manner (1, 7, 11). The putative extracellular region of this protein comprises three immunoglobulin (Ig)-like domains, of which the most amino-terminal, IgV-like domain associates with the ligand CD47, also known as integrin-associated protein (6,12,13).Tyrosine phosphorylation of SHPS-1 is induced by soluble growth factors (1,7,14,15), integrin-mediated cell adhesion (16 -18), or cross-linking of Fc␥ receptors (19). Overexpression of SHPS-1 inhibits the activation of extracellular signal-regulated kinases induced by growth factors such as insulin, epidermal growth factor, and platelet-derived growth factor (7); it also inhibits promotion of the motility and survival of glioblastoma cells by epidermal growth factor (20). Furthermore, SHPS-1 inhibits IgE-induced mediator secretion and cytokine synthesis by mast cells (21). These observations suggest that SHPS-1, presumably by recruiting SHP-1 or SHP-2, negatively modulates a wide range of cellular activation signals initiated by tyrosine kinase-coupled receptors. However, the physiological significance of these observations remains unclear.Recent studies have suggested that SHPS-1, through its association with CD47, contributes to cellular functions that depend on intercellular communication, including T cell activation (13),...