New evidence for a critical role of elastin in calcification of native heart valves: immunohistochemical and ultrastructural study with literature review

Perrotta, Ida; Russo, Emilio; Camastra, Caterina; Filice, G; Mizio, Giulio Di; Colosimo, Federica; Ricci, Pietrantonio; Tripepi, Sandro; Amorosi, Andrea; Triumbari, Franco; Donato, Giuseppe

doi:10.1111/j.1365-2559.2011.03977.x

Cited by 65 publications

(47 citation statements)

References 58 publications

(93 reference statements)

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“…Previous studies have shown that mechanisms of AVD recapitulate developmental programs, suggesting that the dysregulation of specific structural proteins and signaling pathways incite disease and contribute to faulty homeostasis over time and ultimately valve dysfunction later in life (Markwald et al, 2010; Hinton and Yutzey, 2011; Mahler and Butcher, 2011). Elastic fiber fragments, or degradation products, might have pro-angiogenic, pro-proliferative, pro-calcific or pro-inflammatory properties (Perrotta et al, 2011; Pivetta et al, 2014; Parks and Mecham, 2011), in addition to well-described increases in elastase activity (Robinet et al, 2005), suggesting that different elastic fiber fragments have different maladaptive effects. In this context, Emilin1 -deficiency-related EFF results in aberrant angiogenesis and fibrosis, but not calcification.…”

Section: Discussionmentioning

confidence: 99%

TGF-β mediates early angiogenesis and latent fibrosis in an Emilin1-deficient mouse model of aortic valve disease

Munjal

Opoka

Osińska

et al. 2014

Disease Models &Amp; Mechanisms

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Aortic valve disease (AVD) is characterized by elastic fiber fragmentation (EFF), fibrosis and aberrant angiogenesis. Emilin1 is an elastin-binding glycoprotein that regulates elastogenesis and inhibits TGF-β signaling, but the role of Emilin1 in valve tissue is unknown. We tested the hypothesis that Emilin1 deficiency results in AVD, mediated by non-canonical (MAPK/phosphorylated Erk1 and Erk2) TGF-β dysregulation. Using histology, immunohistochemistry, electron microscopy, quantitative gene expression analysis, immunoblotting and echocardiography, we examined the effects of Emilin1 deficiency (Emilin1−/−) in mouse aortic valve tissue. Emilin1 deficiency results in early postnatal cell-matrix defects in aortic valve tissue, including EFF, that progress to latent AVD and premature death. The Emilin1−/− aortic valve displays early aberrant provisional angiogenesis and late neovascularization. In addition, Emilin1−/− aortic valves are characterized by early valve interstitial cell activation and proliferation and late myofibroblast-like cell activation and fibrosis. Interestingly, canonical TGF-β signaling (phosphorylated Smad2 and Smad3) is upregulated constitutively from birth to senescence, whereas non-canonical TGF-β signaling (phosphorylated Erk1 and Erk2) progressively increases over time. Emilin1 deficiency recapitulates human fibrotic AVD, and advanced disease is mediated by non-canonical (MAPK/phosphorylated Erk1 and Erk2) TGF-β activation. The early manifestation of EFF and aberrant angiogenesis suggests that these processes are crucial intermediate factors involved in disease progression and therefore might provide new therapeutic targets for human AVD.

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Section: Discussionmentioning

confidence: 99%

TGF-β mediates early angiogenesis and latent fibrosis in an Emilin1-deficient mouse model of aortic valve disease

Munjal

Opoka

Osińska

et al. 2014

Disease Models &Amp; Mechanisms

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“…Accordingly, it had been shown that ECM structural damage impacts valve durability, leading to allograft degeneration (Schenke-Layland et al, 2009; Lisy et al, 2010). Moreover, it was demonstrated that macrophage metalloproteinase (MMP12)-mediated degradation of elastic fibers contributes to valve mineralization by inducing calcium deposition onto fragmented elastin, which was identified as the initial site of calcification (Perrotta et al, 2011). Emerging evidence suggests that elastin degradation contributes to arterial and aortic valve calcification via the action of macrophage-derived cathepsin S, a highly potent elastase (Aikawa et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Emerging evidence suggests that elastin degradation contributes to arterial and aortic valve calcification via the action of macrophage-derived cathepsin S, a highly potent elastase (Aikawa et al, 2009). Mutations in ELN and microfibril-associated protein genes are known to cause a variety of congenital cardiovascular diseases (Table 1), including Marfan, Beals and Williams-Beuren syndromes, as well as cutis laxa (Curran et al, 1993; Ewart et al, 1993; Loeys et al, 1993; Putnam et al, 1995; Ramirez, 1996; Tassabehji et al, 1998; Loeys et al, 2002; Aikawa et al, 2009; Perrotta et al, 2011). …”

Section: Discussionmentioning

confidence: 99%

Elastogenesis at the onset of human cardiac valve development

et al. 2013

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Semilunar valve leaflets have a well-described trilaminar histoarchitecture, with a sophisticated elastic fiber network. It was previously proposed that elastin-containing fibers play a subordinate role in early human cardiac valve development; however, this assumption was based on data obtained from mouse models and human second and third trimester tissues. Here, we systematically analyzed tissues from human fetal first (4-12 weeks) and second (13-18 weeks) trimester, adolescent (14-19 years) and adult (50-55 years) hearts to monitor the temporal and spatial distribution of elastic fibers, focusing on semilunar valves. Global expression analyses revealed that the transcription of genes essential for elastic fiber formation starts early within the first trimester. These data were confirmed by quantitative PCR and immunohistochemistry employing antibodies that recognize fibronectin, fibrillin 1, 2 and 3, EMILIN1 and fibulin 4 and 5, which were all expressed at the onset of cardiac cushion formation (~week 4 of development). Tropoelastin/elastin protein expression was first detectable in leaflets of 7-week hearts. We revealed that immature elastic fibers are organized in early human cardiovascular development and that mature elastin-containing fibers first evolve in semilunar valves when blood pressure and heartbeat accelerate. Our findings provide a conceptual framework with the potential to offer novel insights into human cardiac valve development and disease.

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“…Calcific aortic stenosis (CAS) is the most common form of valve disease in the Western world, strongly related to aging, and histologically characterized by diffuse fibrous thickening, distortion of the valve leaflet and extensive calcification [1]. Although first described by Monckeberg nearly a century ago, to date little is known regarding the molecular and cellular events that control the stenosing process with only a few reports dealing with the structural appearance of mineralized collagen in the calcifying tissue of native aortic valve [2][3][4].…”

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confidence: 99%

Collagen Mineralization in Human Aortic Valve Stenosis: A Field Emission Scanning Electron Microscopy and Energy Dispersive Spectroscopy Analysis

Perrotta

Davoli

2014

Ultrastructural Pathology

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Calcific aortic stenosis is a slowly progressive disorder characterized by an important extracellular matrix remodeling with fibrosis and massive deposition of minerals (primarily calcium) in the valve leaflet. The main structural components of human aortic valve are the large, thick collagen bundles that withstand the diastolic loading. Collagen has been studied in a number of reports that aim to clarify the mechanisms underlying the structural deterioration of heart valve substitutes, however to date, little is known regarding the morphological interaction between collagen and mineral crystals in the calcifying tissue of native aortic valve. Here, we have analyzed a total of 12 calcified native aortic valves by using scanning electron microscopy (SEM) with Energy Dispersive X-Ray Analysis (EDX) to depict the morphological appearance of mineralized collagen and to determine the location of calcium phosphate minerals in the collagen matrix of the valve cusp. Our results demonstrate that crystals probably nucleate and grow in the interior of the collagen fibers in the absence of surface events.

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New evidence for a critical role of elastin in calcification of native heart valves: immunohistochemical and ultrastructural study with literature review

Abstract: Our results demonstrate the direct involvement of MMP-12 in native aortic valve stenosis. MMP-mediated degradation of elastic fibres might contribute actively to valve mineralization by inducing calcium deposition onto fragmented elastin.

Cited by 65 publications

References 58 publications

TGF-β mediates early angiogenesis and latent fibrosis in an Emilin1-deficient mouse model of aortic valve disease

TGF-β mediates early angiogenesis and latent fibrosis in an Emilin1-deficient mouse model of aortic valve disease

Elastogenesis at the onset of human cardiac valve development

Collagen Mineralization in Human Aortic Valve Stenosis: A Field Emission Scanning Electron Microscopy and Energy Dispersive Spectroscopy Analysis

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