Detection of Osteopontin in Calcified Human Aortic Valves

Mohler, Emile R.; Adam, Leonard P.; McClelland, Pam; Graham, Lori; Hathaway, David R.

doi:10.1161/01.atv.17.3.547

Cited by 167 publications

(106 citation statements)

References 27 publications

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“…Valvular calcium deposits contain both calcium and phosphate 11,57,63,63 as hydroxyapatite, 57,63 the form of calcium-phosphate mineral present in both calcified arterial tissue 64 and bone. Proteins involved in regulation of tissue calcification have been detected in calcified valvular tissue, including osteopontin, 13,14 bone morphogenic proteins (BMPs) 2 and 4, 15 and receptor activator of nuclear factor NF-B ligand (RANKL). 65 Osteoprotegrin (OPG), which prevents mineral resorption in bone tissue, is a soluble decoy receptor that resembles RANK and acts as a competitive inhibitor of RANK binding to RANKL.…”

Section: Calcificationmentioning

confidence: 99%

“…The first was the long-held notion that calcific aortic valve disease was a "degenerative," and therefore unmodifiable, condition. 6 However, more recent studies have demonstrated convincingly that calcific aortic valve lesions have many features characteristic of an active pathobiological process, including chronic inflammation, [7][8][9] lipoprotein deposition, 10 -12 active calcification, [13][14][15][16][17][18] and renin-angiotensin system activation. 19,20 These features are present in both trileaflet and bileaflet aortic valve lesions.…”

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confidence: 99%

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Pathogenesis of Calcific Aortic Valve Disease

O’Brien

2006

ATVB

254

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Background-Over the past 10 to 15 years, calcific aortic valve disease, which includes aortic sclerosis and aortic stenosis, has come to be recognized as an active process, based on: (1) epidemiologic studies demonstrating associations of specific risk factors with increased prevalence or rate of progression of aortic valve disease; (2) identification, in valve lesions, of histopathologic features of chronic inflammation, lipoprotein deposition, renin-angiotensin system components, and molecular mediators of calcification; and (3) identification of cell-signaling pathways and genetic factors that may participate in valve disease pathogenesis. These studies will be reviewed and organized into a proposed global hypothesis for the pathogenesis of calcific aortic valve disease. Key Words: aortic valve disease Ⅲ calcification Ⅲ lipoproteins Ⅲ matrix Ⅲ angiotensin II C alcific aortic valve disease is identified by thickening and calcification of the aortic valve leaflets in the absence of rheumatic heart disease. It is divided, on a functional basis, into aortic sclerosis, in which the leaflets do not obstruct left ventricular outflow, and aortic stenosis, in which obstruction to left ventricular outflow is present. Aortic sclerosis is present in more than 25% of patients over age 65 1 and is associated with a 50% increase risk of cardiovascular events. 2 Aortic stenosis is present in 2% to 5% of very elderly patients, 1,3 is the second most common indication for cardiac surgery, 4 and carries an 80% 5-year risk of progression to heart failure, valve replacement, or death. 5 Though the disease is associated with substantial clinical consequences, there currently is no effective therapy for the disease other than surgical aortic valve replacement.The lack of medical therapies for calcific aortic valve disease can be traced to at least two important issues, one intellectual, the other practical. The first was the long-held notion that calcific aortic valve disease was a "degenerative," and therefore unmodifiable, condition. 6 However, more recent studies have demonstrated convincingly that calcific aortic valve lesions have many features characteristic of an active pathobiological process, including chronic inflammation, 7-9 lipoprotein deposition, 10 -12 active calcification, [13][14][15][16][17][18] and renin-angiotensin system activation. 19,20 These features are present in both trileaflet and bileaflet aortic valve lesions. 21 Also, an emerging body of literature is investigating how genetic factors might influence disease development. [22][23][24][25] The second issue is that, for many years, there were no animal models that faithfully replicated the key histological features of the disease. Recently, rabbit models been developed, 16,26,27 with that of Rajamannan and colleagues already providing a number of novel insights. 16 -18,28,29 In particular, these models have implicated the Wnt 18 and Runx2/ Cbfa1 16,17,27 signaling pathways in disease pathogenesis. Only very recently has a purported mouse model of calcif...

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Section: Calcificationmentioning

confidence: 99%

mentioning

confidence: 99%

Pathogenesis of Calcific Aortic Valve Disease

O’Brien

2006

ATVB

254

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“…OPN is a phosphorylated glycoprotein generated or secreted by osteoblasts, osteoclasts, macrophages, T cells, hematopoietic cells, VSMCs, fibroblasts, and myocardial cells [16] . In calcified human aortic valves, OPN protein expression is upregulated and colocalizes with valvular calcific deposits [17] . OPN and cMGP were found to be expressed at calcification sites within atherosclerotic lesions and in microvessels with Adrenomedullin up-regulates osteopontin and attenuates vascular calcification via the cAMP/PKA signaling pathway www.nature.com/aps Cai Y et al Acta Pharmacologica Sinica npg calciphylaxis [18] .…”

Section: Introductionmentioning

confidence: 99%

Adrenomedullin up-regulates osteopontin and attenuates vascular calcification via the cAMP/PKA signaling pathway

et al. 2010

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Aim: To determine whether adrenomedullin (ADM) attenuates vascular calcification (VC) by inducing osteopontin (OPN) expression.Methods: A VC model of rat aorta was induced with vitamin D3 plus nicotine (VDN), and vascular smooth muscle cell (VSMC) calcification was induced with beta-glycerophosphate. Von Kossa staining and alizarin red staining were assessed. Alkaline phosphatase (ALP) activity was measured. Immunohistochemical analysis was used to detect alpha-actin, while RT-PCR and Western blot analysis were used to quantify OPN expression. Results: Administration of ADM greatly reduced VC in VDN-treated aortas compared with controls, which was confirmed in calcified VSMCs. The decrease in alpha-actin expression was ameliorated by ADM both in vivo and in vitro. Moreover, mRNA and protein expression levels of OPN were significantly up-regulated in calcified aortas, and ADM increased OPN expression in calcified aortas. Furthermore, ADM up-regulated OPN expression in normal aortas and VSMCs. The ADM-mediated effects were similar to that of forskolin, which activates adenylyl cyclase; additionally, while the PKA inhibitor H89 and Ca 2+ chelator Fura-2 blocked the effect of ADM. However, the MEK/ERK inhibitor PD98509 had no effect on ADM induction of OPN mRNA expression. An OPN polyclonal antibody inhibited ADM-mediated attenuation of VC. Conclusion: ADM up-regulates OPN expression and thus attenuates VC via PKA. ADM appears to be an endogenous cardiovascular protective peptide and may represent a new therapeutic target for VC treatment.

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“…Cardiovascular calcification is an age-linked active complex process where oxidized low-density lipoproteins, T-lymphocyte accumulation, autophagic cell death, osteoblast-like differentiation, and osteopontin producing macrophages have been shown to play major roles [11][12][13]. Recently, there has also been a paradigm shift in the understanding of pathogenesis of calcification from a passive atherosclerotic process to an actively regulated one involving activation of osteoblast cells and utilizing similar biochemical processes as in bone formation [14,15].…”

Section: Discussionmentioning

confidence: 99%

A Novel Chemical Solution to Demineralize Vascular Calcification in Ex-Vivo Amputated Limbs

Farres¹,

MH²

2016

J Vasc Med Surg

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The study was performed to evaluate the ex-vivo demineralizing efficacy of a novel chemical solution, combined L(+) lactic acid and D-gluconic acid (LAGA), in calcified peripheral arteries of 2 patients who underwent limb amputation. Angiography was obtained at baseline and after local installation of the 20 ml of LAGA solution in the occluded arteries. A significant dissolution of the calcification with restoration of patency of the occluded arteries was noted. LAGA solution is efficacious in demineralizing calcific peripheral arteries. Our study may pave the way for potential novel therapeutic strategies to treat patients with calcified peripheral arterial disease.

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Detection of Osteopontin in Calcified Human Aortic Valves

Cited by 167 publications

References 27 publications

Pathogenesis of Calcific Aortic Valve Disease

Pathogenesis of Calcific Aortic Valve Disease

Adrenomedullin up-regulates osteopontin and attenuates vascular calcification via the cAMP/PKA signaling pathway

A Novel Chemical Solution to Demineralize Vascular Calcification in Ex-Vivo Amputated Limbs

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