No abstract

Abstract-Apolipoprotein A-II (apoA-II), the second major high-density lipoprotein (HDL) apolipoprotein, has been linked to familial combined hyperlipidemia. Human apoA-II transgenic mice constitute an animal model for this proatherogenic disease. We studied the ability of human apoA-II transgenic mice HDL to protect against oxidative modification of apoB-containing lipoproteins. When challenged with an atherogenic diet, antigens related to low-density lipoprotein (LDL) oxidation were markedly increased in the aorta of 11.1 transgenic mice (high human apoA-II expressor). HDL from control mice and 11.1 transgenic mice were coincubated with autologous very LDL (VLDL) or LDL, or with human LDL under oxidative conditions. The degree of oxidative modification of apoB lipoproteins was then evaluated by measuring relative electrophoretic mobility, dichlorofluorescein fluorescence, 9-and 13-hydroxyoctadecadienoic acid content, and conjugated diene kinetics. In all these different approaches, and in contrast to control mice, HDL from 11.1 transgenic mice failed to protect LDL from oxidative modification. A decreased content of apoA-I, paraoxonase (PON1), and platelet-activated factor acetyl-hydrolase activities was found in HDL of 11.1 transgenic mice. Liver gene expression of these HDL-associated proteins did not differ from that of control mice. In contrast, incubation of isolated human apoA-II with control mouse plasma at 37°C decreased PON1 activity and displaced the enzyme from HDL. Thus, overexpression of human apoA-II in mice impairs the ability of HDL to protect apoB-containing lipoproteins from oxidation. Further, the displacement of PON1 by apoA-II could explain in part why PON1 is mostly found in HDL particles with apoA-I and without apoA-II, as well as the poor antiatherogenic properties of apoA-II-rich HDL.

High pretreatment count of peripheral neutrophils and/or monocytes was independently related with worse prognosis in patients with HNSCC. Classification based on pretreatment neutrophil and monocyte counts enabled the identification of different prognostic profiles. © 2016 Wiley Periodicals, Inc. Head Neck 39: 219-226, 2017.

Summary. Background: Prostaglandin (PG) E 2 induces expression of matrix metalloproteinases and angiogenic factors, thereby contributing to plaque instability. Objective: To study the influence of cyclooxygenase (COX) and PGE synthase (PGES) isoenzyme expression on PGE 2 and PGI 2 biosynthesis in vascular smooth muscle cells (VSMC) in culture. Methods: Cells were treated with human recombinant IL-1b over different periods of time. Expression of PGI synthase, and COX and PGES isoenzymes was determined by real-time reverse transcriptase polymerase chain reaction and immunoblotting. Biosynthesis of prostanoids from exogenous or endogenous substrate was analyzed by high-performance liquid chromatography or enzyme-immunoassay after incubation of cells with labeled arachidonic acid or thrombin, respectively. Results: Cytosolic PGES and microsomal PGES (mPGES) -1 and -2 were expressed in VSMC. PGES activity was mainly linked to mPGES-1. IL-1b induced COX-2 and mPGES-1 with a different time course. VSMC ability to synthesize PGE 2 and PGI 2 fitted mPGES-1 and COX-2 expression, respectively. The ability of VSMC to produce PGI 2 was downregulated by mPGES-1 expression and was restored when mPGES-1 expression was silenced. Results from COX-1 and COX-2 silencing and selective inhibition showed that both COX-1 and COX-2 were involved in the biosynthesis of PGE 2 and their relative contribution depended on the time of incubation with IL-1b. Conclusions: mPGES-1 is the main PGES responsible for PGE 2 biosynthesis by VSMC and its induction downregulates VSMC ability to produce PGI 2. These results support the concept that under inflammatory conditions VSMC could significantly contribute to plaque instability and that mPGES-1 may be a target for therapeutic intervention in patients with cardiovascular risk.