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cytoplasmic domain of tissue factor promotes liver fibrosis in mice

World Journal of Gastroenterology 2017年第31期23卷 5692-5699页

作者： Virginia Knight dinushka lourensz Jorge Tchongue Jeanne Correia Peter Tipping William Sievert Centre for Inflammatory Diseases Department of MedicineSchool of Clinical SciencesMonash University Gastroenterology and Hepatology Unit Monash Health

To evaluate the role of tissue factor (TF) and protease activated receptor (PAR)-2 in liver fibrosis. METHODSUsing CCl4 administration for eight weeks, we induced hepatic fibrosis in wild-type C57BL/6 mice and in mice with deletion of the cytoplasmic signalling domain of TF (TF§CT/§CT), deletion of PAR-2 (PAR-2-/-) and combined deletion of TF signalling domain and PAR-2 (TF§CT/§CT/PAR-2-/-). Hepatic fibrosis area was assessed by quantitative imaging of picrosirius red staining. Hepatic collagen content was assessed by hydroxyproline levels. Hepatic stellate cells (αSMA positive) and hepatic macrophages (CD68 positive) were identified by immunohistochemistry. Hepatic gene expression was determined by PCR and liver TGFβ1 content by ELISA. RESULTSCCl4 treated mice with deletion of the PAR-2 gene (PAR-2-/-) and the cytoplasmic domain of TF (TF§CT/§CT) developed significantly less hepatic fibrosis, characterised by reduced liver fibrosis area and hydroxyproline content, compared to control wildtype mice treated with CCl4. The observed reduction in histological fibrosis was accompanied by a significant decrease in the hepatic content of TGFβ, the prototypic fibrogenic cytokine, as well as fewer activated hepatic stellate cells and hepatic macrophages. Deletion of the TF cytoplasmic signalling domain reduced hepatic fibrosis to levels similar to those observed in mice lacking PAR-2 signalling but combined deletion provided no added protection against fibrosis indicating a lack of mutual modulating effects that have been observed in other contexts such as angiogenic responses. CONCLUSIONTissue factor cytoplasmic domain is involved in TF-PAR-2 signalling initiating hepatic fibrosis and is a potential therapeutic target, as its deletion would not impact coagulation.

关键词： Tissue factor Protease activated receptor Hepatic stellate cell Liver fibrosis Macrophage

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Association between LDL, Apolipoprotein-B Apolipoprotein A-I and Lipoprotein(a) and Severity of Coronary Artery Disease Based on Coronary Angiography

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Journal of Biosciences and Medicines 2015年第8期3卷 53-61页

作者： Pradeep Rasika Perera dinushka Wickramasinghe Hemantha Peiris Lal Chandrasena Vajira Senaratne Department of Biochemistry University of Sri Jayewardenepura Nugegoda Sri Lanka Nawaloka Metropolis Clinical Laboratories Nawaloka Hospitals PLC Colombo Sri Lanka Cardiology Unit National Hospital Colombo Sri Lanka

Atherosclerosis is the most important contributor to increasing burden of coronary artery disease (CAD). Growing evidence suggests that the ratios of Apo B/Apo A-I and Lp(a) are better indexes for risk assessment of CAD. Elevated plasma levels of lipoprotein(a) in humans represent a major in-herited risk factor for atherosclerosis. Thus, a study was performed to determine the association betwwen serum Apo B, Apo A-I, and lipoprotein(a) levels, and severity of CAD in patients with CAD confirmed on coronary angiography findings. An analytical case control study was carried out with 85 patients (58 males and 27 females) 40 - 60 years of age confirmed as having CAD on coronary angiography and 85 age and sex matched healthy volunteers as controls. Serum samples were an-alyzed for Apo A-1 LDL, Apo B, Apo A-I, and lipoprotein(a) concentration and the severity of CAD was assessed using coronary angiography scoring method. Patients with CAD had significantly high serum LDL-C, Apo B and Lp(a) levels compared to control subjects. However, serum Apo A-I level did not show a significant difference between two groups. Subjects with a positive family history of CAD with increased serum Lp(a) ≥ 17.3 mg/dL have high risk for development of CAD. Present study suggests that serum Lp(a) cut-off value of 17.3 mg/dL may be an important predictor in ruling out major vessel disease and luminal narrowing by atheroma.

关键词： Coronary Artery Disease Apo B Apo A-I LDL-C Lp(a) Coronary Angiography Score

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