The role of transforming growth factor-β in atherosclerosis

Transforming growth factor-β (TGF-β) plays a pivotal role in a range of biological processes, including the control of cellular proliferation and differentiation, regulation of tissue repair and extracellular matrix accumulation, and modulation of the immune and inflammatory responses. The role of TGF-β in the pathogenesis of atherosclerosis, which is widely perceived as a form of chronic inflammation, has been the subject of debate for a number of years. A pro-atherogenic role was suspected because of its ability to promote fibrosis and to inhibit endothelial regeneration. However, several recent studies have shown that TGF-β limits atherosclerosis by modulating a number of processes, including the accumulation of lipids in the vessel wall and the inflammatory response. This review will discuss the role of TGF-β in atherosclerosis along with the molecular mechanisms underlying its action during the pathogenesis of the disease

Transforming growth factor-β-induced expression of the apolipoprotein e gene requires c-Jun N-terminal kinase, p38 kinase, and casein kinase 2

Objective— The cytokine transforming growth factor-β (TGF-β) and apolipoprotein E (apoE) play potent antiatherogenic roles. Despite such importance, the mechanisms underlying the regulation of apoE expression by TGF-β have not been characterized and were therefore investigated. Methods and Results— Using THP-1 cell line as a model system, with key findings confirmed in primary cultures, we show that TGF-β induces the expression of apoE, and this is prevented by pharmacological inhibitors of c-Jun N-terminal kinase (JNK), p38 kinase, and casein kinase 2 (CK2). In support for an important role for these pathways, TGF-β activates JNK, p38 kinase, and CK2, and dominant-negative (DN) forms of these proteins inhibit the cytokine-induced apoE expression. TGF-β also increases the phosphorylation and expression of c-Jun, a downstream target for JNK action and a component of activator protein-1 (AP-1), and DN c-Jun inhibits the induction of apoE expression in response to the cytokine. AP-1 DNA binding was also induced by TGF-β, and the action of p38 kinase, JNK, and CK2 converged on the activation of c-Jun/AP-1. Conclusions— These studies reveal a novel role for JNK, p38 kinase, CK2, and c-Jun/AP-1 in the TGF-β–induced expression of apoE

Critical role for casein kinase 2 and phosphoinositide-3-kinase in the interferon- -induced expression of monocyte chemoattractant protein-1 and other key genes implicated in atherosclerosis

Objective— The interferon-γ (IFN-γ)–mediated regulation of macrophage gene expression is of crucial importance in the pathogenesis of atherosclerosis. The mechanisms underlying the actions of IFN-γ signaling in macrophages were investigated using monocyte chemoattractant protein (MCP)-1 as a model gene. Methods and Results— The IFN-γ–induced expression of MCP-1 in macrophages was attenuated by inhibitors of phosphoinositide-3-kinase (PI3K), casein kinase 2 (CK2), and Janus kinase (JAK)-2. AKT was the downstream target for PI3K action. Electrophoretic mobility shift assays and chromatin immunoprecipitation showed that signal transducer and activator of transcription (STAT)-1 interacted with IFN-γ responsive elements in the MCP-1 gene promoter. The IFN-γ–induced activity of the MCP-1 gene promoter and an artificial promoter containing STAT1 responsive elements was inhibited by expression of dominant negative forms of JAK-1 and -2, STAT1, CK2, and AKT. The action of CK2 and AKT on STAT1 activation was mediated, at least in part, through the regulation of serine 727 phosphorylation. Analysis of a number of other genes regulated by this cytokine and implicated in atherosclerosis revealed a gene-specific action for PI3K/AKT in IFN-γ signaling. Conclusions— These studies provide novel insights into the role of PI3K/AKT and CK2 in IFN-γ signaling relevant to changes in macrophage gene expression during atherosclerosis

Approximation Degree of Durrmeyer-Bézier Type Operators

Recently, a mixed hybrid operator, generalizing the well-known Phillips operators and Baskakov-Szász type operators, was introduced. In this paper, we study Bézier variant of these new operators. We investigate the degree of approximation of these operators by means of the Lipschitz class function, the modulus of continuity, and a weighted space. We study a direct approximation theorem by means of the unified Ditzian-Totik modulus of smoothness. Furthermore, the rate of convergence for functions having derivatives of bounded variation is discussed