FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W203356579> ?p ?o ?g. }

• W203356579 abstract "Rupture of Abdominal Aortic Aneurysm (AAA) is the end-stage, catastrophic failure of the aneurysmal aortic wall and is associated with a mortality rate of up to 95 percent. Presently, surgery is the only treatment option available but carries with it a mortality rate of up to five percent and is usually reserved for repair of aneurysms showing high probability of rupture. What is required for the treatment of AAA, and essentially the basis of research in this area, is to understand the pathology of the disease well enough so that non-surgical intervention aimed at inhibiting small aneurysm progression can be developed. The lack of non-invasive medical treatment for the disease, especially at the initial stages of development, stems from an incomplete understanding of its pathogenesis. Despite extensive laboratory and clinical research, the precise mechanisms leading to aneurysm formation remain unclear. The hallmark features of an aneurysmal aortic wall are degradation and fragmentation of the medial extracellular matrix (ECM), and significant reduction in smooth muscle cell (SMC) density, believed to be associated with the marked cellular inflammatory response also observed in the aneurysmal tissue. A newly identified member of the tumour necrosis factor receptor superfamily known as osteoprotegerin (OPG) is constitutively expressed within the human artery wall and, under pathological conditions, is upregulated and associated with vascular disease. Elaboration on the involvement OPG of in AAA will determine its potential as a pharmacological target for the treatment of aneurysmal disease. The focus of this study was to understand whether OPG might be important in the development of AAA. Two hypotheses were proposed:1. Expression of OPG is upregulated in the aneurysmal aorta2. Osteoprotegerin actively promotes aneurysm phenotype within the aortic wall The specific aims of the study were to:a) Assess relationship between aortic concentration of OPG and the presence of aneurysmb) Define possible mechanism(s) by which OPG may be functionally active in the promotion of aneurysm developmentc) Modulate aortic expression of OPG and assess the effect on aneurysm developmentSerum OPG was correlated with aneurysm growth rate in 146 men with small AAA followed by ultrasound for 3 years (R=0.20; P=0.04), and a demonstrated predictor of aneurysm expansion on multiple-regression analysis (P=0.02; coefficient 1.33, SE 0.51) in a model consisting of patient age, diabetic status, smoking history, initial aortic diameter, serum cholesterol, and C-reactive protein. Western analysis showed 3-fold, 8-fold, and 12-fold greater OPG concentrations in human AAA biopsies compared to age and gender-matched atherosclerotic narrowed aorta (AOD; 1.4±0.1 ng/mg tissue vs 0.5±0.1 ng/mg tissue; P=0.002), post-mortem non-diseased abdominal aorta (PAA; 1.4±0.1 ng/mg tissue vs 0.2±0.1 ng/mg tissue; P<0.001), and non-diseased thoracic aorta (TA; 1.4±0.1 ng/mg tissue vs 0.1±0.06 ng/mg tissue; P<0.001), respectively. Resident vascular smooth muscle cells (VSMC) and infiltrating macrophages were identified as primary sources for OPG within the aneurysmal aortic media. The association between aortic expression of OPG and the presence of AAA was confirmed in an animal model of experimental aneurysm formation, in which levels of OPG protein were 4-fold greater in aneurysmal aortic tissue compared to non-aneurysmal tissue. Furthermore, aortic tissue levels of OPG in this model correlated strongly with vessel diameter.Healthy human aortic VSMC incubated with recombinant human OPG (0-20 ng rhOPG/10 ⁵ cells/ml/24h) developed an aneurysmal phenotype defined by dose-dependent impaired cell proliferation (P<0.001), increased apoptosis (P<0.01), decreased interleukin (IL)-6 expression (P<0.001), and increased matrix metalloproteinase (MMP)-9 activity (P=0.01). Gene expression in OPG-treated VSMC reflected these results exhibiting down-regulation of genes associated with cell growth and survival, and up-regulation of genes that negatively regulate cell growth and promote cell death. Incubation of human monocytic cells with OPG (0-20 ng rhOPG/10 ⁵ cells/ml/24h) resulted in up to a 2-fold dose-dependent increase in IL-6 production in lipopolysaccharide (LPS)-activated cells (P=0.005). In addition, OPG (1 ng/10 ⁵ cells/ml/24h) acted to induce a 2-fold increase in MMP-9 expression (P<0.001), with a 1.5-fold increase in MMP-2 production (P=0.01) in resting human monocytic cells. Treatment of human AAA tissue in culture with the angiotensin II receptor blocker, Irbesartan, and the peroxisome proliferator-activated receptor gamma (PPARγ) ligands, Pioglitazone and Rosiglitazone, inhibited OPG production by up to 50%, as well as reducing inflammatory cytokine, and proteolytic enzyme production. The effects produced by thiazolidinedione treatment on aneurysm tissue ex vivo were reproduced in vivo. Both aortic expression of OPG and MMP activity within aortic tissue from a mouse model of experimental aneurysm formation were down-regulated significantly with Pioglitazone medication. This study demonstrates for the first time the association of OPG with AAA and identifies a possible key role for the protein in the promotion of an aneurysmal phenotype within the normal aortic wall. The ability of existing medication to limit this action potentially opens a therapeutic pathway through which to limit aneurysm expansion in humans by targeting arterial expression of OPG." @default.
• W203356579 created "2016-06-24" @default.
• W203356579 creator A5039634269 @default.
• W203356579 date "2006-01-01" @default.
• W203356579 modified "2023-09-27" @default.
• W203356579 title "Osteoprotegerin: a pathological role in human abdominal aortic aneurysm" @default.
• W203356579 cites W103159710 @default.
• W203356579 cites W106779205 @default.
• W203356579 cites W1491678226 @default.
• W203356579 cites W1494386735 @default.
• W203356579 cites W1495994935 @default.
• W203356579 cites W1510237891 @default.
• W203356579 cites W1532879827 @default.
• W203356579 cites W1534645474 @default.
• W203356579 cites W1537686225 @default.
• W203356579 cites W1538233442 @default.
• W203356579 cites W1541823805 @default.
• W203356579 cites W1545561369 @default.
• W203356579 cites W1565818905 @default.
• W203356579 cites W1574330564 @default.
• W203356579 cites W1583489560 @default.
• W203356579 cites W1583731895 @default.
• W203356579 cites W1584270516 @default.
• W203356579 cites W1587697394 @default.
• W203356579 cites W1596678070 @default.
• W203356579 cites W1602981281 @default.
• W203356579 cites W1616121322 @default.
• W203356579 cites W1633340712 @default.
• W203356579 cites W1639924204 @default.
• W203356579 cites W1654947539 @default.
• W203356579 cites W1657827244 @default.
• W203356579 cites W1668309971 @default.
• W203356579 cites W166917290 @default.
• W203356579 cites W1669342624 @default.
• W203356579 cites W1707451623 @default.
• W203356579 cites W1808180572 @default.
• W203356579 cites W1845459216 @default.
• W203356579 cites W1894541755 @default.
• W203356579 cites W1914602305 @default.
• W203356579 cites W1915352327 @default.
• W203356579 cites W1935587632 @default.
• W203356579 cites W1942214720 @default.
• W203356579 cites W1953160336 @default.
• W203356579 cites W1961909698 @default.
• W203356579 cites W1963554804 @default.
• W203356579 cites W1964617786 @default.
• W203356579 cites W1966039015 @default.
• W203356579 cites W1966347912 @default.
• W203356579 cites W1966933286 @default.
• W203356579 cites W1967031118 @default.
• W203356579 cites W1967958678 @default.
• W203356579 cites W1968126995 @default.
• W203356579 cites W1968500926 @default.
• W203356579 cites W1968618681 @default.
• W203356579 cites W1969345355 @default.
• W203356579 cites W1970559524 @default.
• W203356579 cites W1971266242 @default.
• W203356579 cites W1971448058 @default.
• W203356579 cites W1971720206 @default.
• W203356579 cites W1971944129 @default.
• W203356579 cites W1973030145 @default.
• W203356579 cites W1973047758 @default.
• W203356579 cites W1973061804 @default.
• W203356579 cites W1974471520 @default.
• W203356579 cites W1974484280 @default.
• W203356579 cites W1974659965 @default.
• W203356579 cites W1974692755 @default.
• W203356579 cites W1975405608 @default.
• W203356579 cites W1976008108 @default.
• W203356579 cites W1976019589 @default.
• W203356579 cites W1976537349 @default.
• W203356579 cites W1976562969 @default.
• W203356579 cites W1976837011 @default.
• W203356579 cites W1977013832 @default.
• W203356579 cites W1977732231 @default.
• W203356579 cites W1977835740 @default.
• W203356579 cites W1977993838 @default.
• W203356579 cites W1978396088 @default.
• W203356579 cites W1978582021 @default.
• W203356579 cites W1979026008 @default.
• W203356579 cites W1979390430 @default.
• W203356579 cites W1979671850 @default.
• W203356579 cites W1979761686 @default.
• W203356579 cites W1980418071 @default.
• W203356579 cites W1980480613 @default.
• W203356579 cites W1981106016 @default.
• W203356579 cites W1981625589 @default.
• W203356579 cites W1983678692 @default.
• W203356579 cites W1984989820 @default.
• W203356579 cites W1985768272 @default.
• W203356579 cites W1986316605 @default.
• W203356579 cites W1987280936 @default.
• W203356579 cites W1988757615 @default.
• W203356579 cites W1991873795 @default.
• W203356579 cites W1992966949 @default.
• W203356579 cites W1993573575 @default.
• W203356579 cites W1994632041 @default.
• W203356579 cites W1994756823 @default.
• W203356579 cites W1995369191 @default.
• W203356579 cites W1995471855 @default.

• next