Association of Osteoprotegerin With Human Abdominal Aortic Aneurysm Progression

Moran, Corey S.; McCann, Moira; Karan, Mirko; Norman, Paul; Ketheesan, Natkunam; Golledge, Jonathan

doi:10.1161/circulationaha.104.464727

Cited by 149 publications

(165 citation statements)

References 29 publications

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“…It is therefore possible that reduced MMP-9 activity is partially responsible for the increased connective tissue content of the lesions in OPG Ϫ/Ϫ .apoE Ϫ/Ϫ mice. In keeping with our current observations, it has recently been demonstrated that OPG treatment induces MMP-9 activity 34 and increases total MMP activity 35 in cultured human SMCs.…”

Section: Bennett Et Al Opg Atherosclerosis and Calcificationsupporting

confidence: 92%

Osteoprotegerin Inactivation Accelerates Advanced Atherosclerotic Lesion Progression and Calcification in Older ApoE ^−/− Mice

Bennett

Scatena

Kirk

et al. 2006

ATVB

286

206

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Objective-Osteoprotegerin (OPG), a member of the tumor necrosis factor (TNF) superfamily of proteins, plays an important role in bone remodeling and is expressed in both mouse and human atherosclerotic lesions. The current study was designed to assess whether OPG plays a role in the progression and calcification of advanced atherosclerotic lesions in apoE Ϫ/Ϫ mice. Methods and Results-Atherosclerotic lesion area and composition and aortic calcium content were examined in mice deficient in both OPG and apolipoprotein E (OPG Ϫ/Ϫ .apoE Ϫ/Ϫ mice) at 20, 40, and 60 weeks of age. Littermate OPG ϩ/ϩ .apoE Ϫ/Ϫ mice were used as controls. The average cross-sectional area of lesions in the innominate arteries was increased in OPG Ϫ/Ϫ .apoE Ϫ/Ϫ mice at 40 and 60 weeks of age. The increase in lesion area was coupled with a reduced cellularity and an increase in connective tissue including laminated layers of elastin. Sixty-week-old OPG Ϫ/Ϫ .apoEmice also had an increase in the area of calcification of the lesions. There were no differences in markers of plaque stability. In vitro, OPG induced matrix metalloproteinase-9 (MMP-9) activity in macrophages and smooth muscle cells and acted as a survival factor for serum-deprived smooth muscle cells. Conclusion-OPG inhibits advanced plaque progression by preventing an increase in lesion size and lesion calcification.OPG may act as a survival factor and may modulate MMP9 production in vascular cells.

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Section: Bennett Et Al Opg Atherosclerosis and Calcificationsupporting

confidence: 92%

Osteoprotegerin Inactivation Accelerates Advanced Atherosclerotic Lesion Progression and Calcification in Older ApoE ^−/− Mice

Bennett

Scatena

Kirk

et al. 2006

ATVB

286

206

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“…The early impairment of nitric oxide release is a key feature of endothelial dysfunction, which invariably precedes permanent vascular alterations. 35 Our results also suggest a mechanism to explain why altered serum OPG levels have been shown to reflect the development or status of vascular disease in both diabetic and nondiabetic patients, [13][14][15][16][17][18][19][20][21][22][23][24] indicating that therapeutic strategies aimed to decrease the OPG serum levels may be suitable for improving the vascular function in diabetes mellitus and possibly in other vascular pathologies characterized by a chronic inflammatory state.…”

Section: Discussionmentioning

confidence: 87%

“…[17][18][19][20] Moreover, it has been demonstrated that up-regulated serum OPG levels have a negative prognostic value in heart failure after acute myocardial infarction as well as in patients affected by abdominal aortic aneurysm. [21][22][23] Interestingly, it has also been shown that the levels of free RANKL are significantly decreased in the sera of patients affected by coronary artery disease 24 as well as in the endomyocardium in transplant coronary artery disease. 25 The aim of this study was to investigate whether serum OPG elevation represents an early or a late event in the natural history of diabetes mellitus and to investigate the correlation between OPG production/release and glycemic levels both in vivo and in vitro.…”

mentioning

confidence: 99%

An Increased Osteoprotegerin Serum Release Characterizes the Early Onset of Diabetes Mellitus and May Contribute to Endothelial Cell Dysfunction

Secchiero

Corallini

Pandolfi

et al. 2006

The American Journal of Pathology

130

105

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Serum osteoprotegerin (OPG) is significantly increased in diabetic patients, prompting expanded investigation of the correlation between OPG production/release and glycemic levels. Serum levels of OPG, but not of its cognate ligand receptor activator of nuclear factor-B ligand (RANKL), were significantly increased in type 2 diabetes mellitus patients compared with healthy blood donors. Serum OPG was also significantly elevated in a subgroup of recently diagnosed diabetic patients (within 2 years). The relationship between serum OPG and diabetes mellitus onset was next investigated in apoE-null and littermate mice. Serum OPG increased early after diabetes induction in both mouse strains and showed a positive correlation with blood glucose levels and an inverse correlation with the levels of free (OPG-unbound) RANKL. The in vitro addition of tumor necrosis factor-␣ to human vascular endothelial cells, but not human peripheral blood mononuclear cells, markedly enhanced OPG release in culture. In contrast, high glucose concentrations did not modulate OPG release when used alone or in association with tumor necrosis factor-␣. Moreover, the ability of soluble RANKL to activate the extracellular signal-regulated kinase/mitogen-activated protein kinase and endothelial nitric-oxide synthase pathways in endothelial cells was neutralized by preincubation with recombinant OPG. Altogether, these findings suggest that increased OPG production represents an early Receptor activator of nuclear factor (NF)-B ligand (RANKL) is a member of the tumor necrosis factor (TNF) family of cytokines, which exists either as type II membrane or as soluble protein.1 RANKL was originally described as being expressed by activated T lymphocytes and osteoblasts, and it has been involved in the interaction between T lymphocytes and dendritic cells, osteoclast differentiation from monocytic precursor cells, and activation of mature osteoclasts.1-6 Two receptors for RANKL have been identified: transmembrane RANK and soluble osteoprotegerin (OPG).2,3,5 RANK mRNA is ubiquitously expressed in human tissues, but RANK protein expression has been characterized only in normal dendritic cells, CD4 and CD8 T lymphocytes, osteoclast monocytic precursors, and endothelial cells, suggesting that expression of this protein is posttranscriptionally regulated. 6 For the purpose of this study, it is noteworthy that, by interacting with RANK, RANKL induces a variety of biological effects on endothelial cells, such as promotion of cell survival and angiogenesis. [7][8][9] Although the affinity of RANKL for OPG is weaker than that for RANK,5 when present at high concentrations soluble OPG prevents RANKL interaction with transmembrane RANK, thus acting as a decoy receptor. 3,5 It has been shown that OPG is produced by a wide range of tissues, including the cardiovascular system, and that OPG levels are particularly high in aortic and renal arteries. 10 -12 Interestingly, different groups of investigators have reported that serum OPG is significantly increased in both t...

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“…Other included biomarkers that have not been mentioned above are markers in the field of connective tissue,41 lipids,42, 43 the immune system,44, 45, 46, 47, 48, 49, 50, 51 kidney function,52, 53 and hormones54, 55 (see Table 1). …”

Section: Resultsmentioning

confidence: 99%

Systematic Review of Circulating, Biomechanical, and Genetic Markers for the Prediction of Abdominal Aortic Aneurysm Growth and Rupture

Groeneveld

Meekel

Rubinstein

et al. 2018

JAHA

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BackgroundThe natural course of abdominal aortic aneurysms (AAA) is growth and rupture if left untreated. Numerous markers have been investigated; however, none are broadly acknowledged. Our aim was to identify potential prognostic markers for AAA growth and rupture.Methods and ResultsPotential circulating, biomechanical, and genetic markers were studied. A comprehensive search was conducted in PubMed, Embase, and Cochrane Library in February 2017, following Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines. Study selection, data extraction, and methodological quality assessment were conducted by 2 independent researchers. Plausibility of markers was based on the amount of publications regarding the marker (more than 3), pooled sample size (more than 100), bias risk and statistical significance of the studies. Eighty‐two studies were included, which examined circulating (n=40), biomechanical (n=27), and genetic markers (n=7) and combinations of markers (n=8). Factors with an increased expansion risk included: AAA diameter (9 studies; n=1938; low bias risk), chlamydophila pneumonia (4 studies; n=311; medium bias risk), S‐elastin peptides (3 studies; n=205; medium bias risk), fluorodeoxyglucose uptake (3 studies; n=104; medium bias risk), and intraluminal thrombus size (5 studies; n=758; medium bias risk). Factors with an increased rupture risk rupture included: peak wall stress (9 studies; n=579; medium bias risk) and AAA diameter (8 studies; n=354; medium bias risk). No meta‐analysis was conducted because of clinical and methodological heterogeneity.ConclusionsWe identified 5 potential markers with a prognostic value for AAA growth and 2 for rupture. While interpreting these data, one must realize that conclusions are based on small sample sizes and clinical and methodological heterogeneity. Prospective and methodological consonant studies are strongly urged to further study these potential markers.

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Association of Osteoprotegerin With Human Abdominal Aortic Aneurysm Progression

Cited by 149 publications

References 29 publications

Osteoprotegerin Inactivation Accelerates Advanced Atherosclerotic Lesion Progression and Calcification in Older ApoE ^−/− Mice

Osteoprotegerin Inactivation Accelerates Advanced Atherosclerotic Lesion Progression and Calcification in Older ApoE ^−/− Mice

An Increased Osteoprotegerin Serum Release Characterizes the Early Onset of Diabetes Mellitus and May Contribute to Endothelial Cell Dysfunction

Systematic Review of Circulating, Biomechanical, and Genetic Markers for the Prediction of Abdominal Aortic Aneurysm Growth and Rupture

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Association of Osteoprotegerin With Human Abdominal Aortic Aneurysm Progression

Cited by 149 publications

References 29 publications

Osteoprotegerin Inactivation Accelerates Advanced Atherosclerotic Lesion Progression and Calcification in Older ApoE −/− Mice

Osteoprotegerin Inactivation Accelerates Advanced Atherosclerotic Lesion Progression and Calcification in Older ApoE −/− Mice

An Increased Osteoprotegerin Serum Release Characterizes the Early Onset of Diabetes Mellitus and May Contribute to Endothelial Cell Dysfunction

Systematic Review of Circulating, Biomechanical, and Genetic Markers for the Prediction of Abdominal Aortic Aneurysm Growth and Rupture

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Product

Resources

About

Osteoprotegerin Inactivation Accelerates Advanced Atherosclerotic Lesion Progression and Calcification in Older ApoE ^−/− Mice

Osteoprotegerin Inactivation Accelerates Advanced Atherosclerotic Lesion Progression and Calcification in Older ApoE ^−/− Mice