Cytochrome P450 epoxygenases, soluble epoxide hydrolase, and the regulation of cardiovascular inflammation.
ABSTRACT The cytochrome P450 (CYP) epoxygenase enzymes CYP2J and CYP2C catalyze the epoxidation of arachidonic acid to epoxyeicosatrienoic acids (EETs), which are rapidly hydrolyzed to dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). It is well-established that CYP epoxygenase-derived EETs possess potent vasodilatory effects; however, the cellular effects of EETs and their regulation of various inflammatory processes have become increasingly appreciated in recent years, suggesting that the role of this pathway in the cardiovascular system extends beyond the maintenance of vascular tone. In particular, CYP epoxygenase-derived EETs inhibit endothelial activation and leukocyte adhesion via attenuation of nuclear factor-kappaB activation, inhibit hemostasis, protect against myocardial ischemia-reperfusion injury, and promote endothelial cell survival via modulation of multiple cell signaling pathways. Thus, the CYP epoxygenase pathway is an emerging target for pharmacological manipulation to enhance the cardiovascular protective effects of EETs. This review will focus on the role of the CYP epoxygenase pathway in the regulation of cardiovascular inflammation and (1) describe the functional impact of CYP epoxygenase-derived EET biosynthesis and sEH-mediated EET hydrolysis on key inflammatory process in the cardiovascular system, (2) discuss the potential relevance of this pathway to pathogenesis and treatment of cardiovascular disease, and (3) identify areas for future research.
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ABSTRACT: Detection of HCV infection during the window phase of infection, before seroconversion, is important in blood screening. However, a significant delay exists between the time of infection and the development of antibodies. The delay in window period can last up to 70 days. The aim of the present study was to investigate the kinetics of HCV markers during early infection, with detection of HCV core antigen as an early method for diagnosis. The study included determination of HCV RNA by qualitative and quantitative PCR, HCV core antigen detection by enzyme linked immunosorbent assay (ELISA) and specific serological markers including anti-HCV IgG and IgM. The study was carried out on 34 patients diagnosed as non A non B acute hepatitis and proved to be hepatitis C by qualitative HCV RNA PCR. Sixteen healthy control subjects were also included. From each consenting patient and control, blood samples were collected and serum was separated and subjected to determination of AST and ALT and the following virological laboratory tests: HCV core antigen detection by ELISA, determination of specific anti-HCV IgM and specific anti-HCV IgG, qualitative and quantitative determination of HCV RNA by second version of PCR. In patients, the median quantity of HCV RNA was 739.1 x 10(3) lu/ml with minimum quantity 2.1 x 10(3) lu/ml and maximum 38352.3 x 10(3) lu/ml. A comparison between the different diagnostic methods revealed that the highest sensitivity was for HCV-core antigen detection (82.4%), specificity was 100% negative predictive value was 72.2% and positive predictive value was 100%. Specific anti-HCV IgG had moderate levels of sensitivity (58.5%), specificity (75%), negative predictive value (46.2%)and positive predictive value (83.3%). The least sensitive method was the specific anti-HCV IgM (29.4%) with negative predictive value 40% but had specificity and positive predictive value of 100% of each. From this study we could conclude the followings: From virological methods, serological detection of specific IgM anti-HCV had the least sensitivity limits, while it had the highest specificity and positive predictive value. Specific anti-HCV IgG had moderate sensitivity and specificity. The most sensitive and specific tool for diagnosis of early HCV viraemia was the detection of HCV core Ag by ELISA when compared to molecular biological methods.The Egyptian journal of immunology / Egyptian Association of Immunologists 02/2004; 11(1):123-9.
Article: c-Myc is essential for hematopoietic stem cell differentiation and regulates Lin(-)Sca-1(+)c-Kit(-) cell generation through p21.[show abstract] [hide abstract]
ABSTRACT: The c-Myc protein is a member of the basic region/helix-loop-helix/leucine zipper (bHLHZip) transcription factor family, which is implicated in regulation of proliferation, differentiation, and apoptosis in multiple cell types. The aim of this study was to characterize the role of the proto-oncogene c-myc in hematopoietic stem cells (HSC) during postnatal development. We have generated a conditional mouse model that allows us to inactivate c-myc in bone marrow (BM) in an inducible fashion. We show that conditional inactivation of c-Myc in BM severely impairs HSC differentiation, leading to a striking decrease in the number of lymphoid and myeloid cells. c-Myc deletion in BM causes substantial accumulation of a Lin(-)Sca-1(+)c-Kit(-) cell population expressing high levels of the cell-cycle inhibitor p21, whose origin and function are otherwise poorly characterized. In vivo inactivation of p21 and c-Myc normalizes Lin(-)Sca-1(+)c-Kit(-) cell numbers and restores normal proliferation. The potential origin and function of these cells are discussed. c-Myc plays a role in HSC maintenance and differentiation and might be regulating generation of Lin(-)Sca-1(+)c-Kit(-) through the cell-cycle regulator p21.Experimental Hematology 10/2007; 35(9):1333-43. · 2.90 Impact Factor
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ABSTRACT: In most arterial beds a significant endothelium-dependent dilation to various stimuli persists even after inhibition of nitric oxide synthase and cyclo-oxygenase. This dilator response is preceded by an endothelium-dependent hyperpolarization of vascular smooth muscle cells, which is sensitive to a combination of the calcium-dependent potassium-channel inhibitors charybdotoxin and apamin, and is assumed to be mediated by an unidentified endothelium-derived hyperpolarizing factor (EDHF). Here we show that the induction of cytochrome P450 (CYP) 2C8/34 in native porcine coronary artery endothelial cells by beta-naphthoflavone enhances the formation of 11,12-epoxyeicosatrienoic acid, as well as EDHF-mediated hyperpolarization and relaxation. Transfection of coronary arteries with CYP 2C8/34 antisense oligonucleotides results in decreased levels of CYP 2C and attenuates EDHF-mediated vascular responses. Thus, a CYP-epoxygenase product is an essential component of EDHF-mediated relaxation in the porcine coronary artery, and CYP 2C8/34 fulfils the criteria for the coronary EDHF synthase.Nature 10/1999; 401(6752):493-7. · 36.28 Impact Factor