Fibrillin‐1 genetic deficiency leads to pathological ageing of arteries in mice

Mariko, Boubacar; Pezet, Mylène; Escoubet, Brigitte; Bouillot, Stéphanie; Andrieu, Jean-Pierre; Starcher, Barry; Quaglino, Daniela; Jacob, Marie‐Paule; Huber, Philippe; Ramirez, Francesco; Faury, Gilles

doi:10.1002/path.2840

Cited by 48 publications

(43 citation statements)

References 49 publications

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“…Previous work demonstrates that fibrillin-1 deficiency leads to increased aortic diameter pressure curves, hypotension, fragmentation of elastin, and changes in aortic compliance that becomes apparent with age (44,45). Our findings also show increases in aortic diameter pressure curves in 6-month-old MAGP DKO mice but not in the single knockouts.…”

Section: Discussionsupporting

confidence: 72%

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Microfibril-associated Glycoprotein 2 (MAGP2) Loss of Function Has Pleiotropic Effects in Vivo

Combs¹,

Knutsen²,

Broekelmann³

et al. 2013

Journal of Biological Chemistry

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show abstract

Section: Discussionsupporting

confidence: 72%

“…Secondly, ECM remodeling and homeostasis may be altered by loss of MAGPs. Increased TGF␤ signaling in aortic tissue occurs with loss of growth factor binding by microfibril proteins (3,44,48). This leads to extensive pathological remodeling, loss of vessel integrity, and, ultimately, aortic dissection in mice and humans in vivo (3,48,49).…”

Section: Discussionmentioning

confidence: 99%

Microfibril-associated Glycoprotein 2 (MAGP2) Loss of Function Has Pleiotropic Effects in Vivo

Combs¹,

Knutsen²,

Broekelmann³

et al. 2013

Journal of Biological Chemistry

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“…The boxed area in a is shown at higher magnification in the confocal fluorescent images presented in photo segments which depict the localization of b perlecan c elastin and d cell nuclei in the ACL sections. Perlecan and elastin are colocalized to short fibrillar material in the ACL in the merged image (e) pathological ageing of arteries in mice (Mariko et al 2011). Elastic microfibrils have a particularly important role to play in arterial development and also provide compliance properties in mature vessels (Carta et al 2009).…”

Section: Discussionmentioning

confidence: 99%

Colocalization in vivo and association in vitro of perlecan and elastin

Hayes

Lord

Smith

et al. 2011

Histochem Cell Biol

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We have colocalized elastin and fibrillin-1 with perlecan in extracellular matrix of tensional and weight-bearing connective tissues. Elastin and fibrillin-1 were identified as prominent components of paraspinal blood vessels, and posterior longitudinal ligament in the human fetal spine and outer annulus fibrosus of the fetal intervertebral disc. We also colocalized perlecan with a synovial elastic basal lamina, where the attached synovial cells were observed to produce perlecan. Elastin, fibrillin-1 and perlecan were co-localized in the intima and media of small blood vessels in the synovium and in human fetal paraspinal blood vessels. Elastic fibers were observed at the insertion point of the anterior cruciate ligament to bone in the ovine stifle joint where they colocalized with perlecan. Elastin has not previously been reported to be spatially associated with perlecan in these tissues. Interactions between the tropoelastin and perlecan heparan sulfate chains were demonstrated using quartz crystal microbalance with dissipation solid phase binding studies. Electrostatic interactions through the heparan sulfate chains of perlecan and core protein mediated the interactions with tropoelastin, and were both important in the coacervation of tropoelastin and deposition of elastin onto perlecan immobilized on the chip surface. This may help us to understand the interactions which are expected to occur in vivo between the tropoelastin and perlecan to facilitate the deposition of elastin and formation of elastic microfibrils in situ and would be consistent with the observed distributions of these components in a number of connective tissues.

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“…Insoluble elastin, mainly synthesized during development and postnatal growth, is associated with fibrillin-1, the major component of extracellular microfibrils, and a regulator of elastogenesis. 26 Whether aneurysm formation results from an early defect in elastogenesis or a later disruption of mature elastic fibers is unclear. In this study, we report that ELN levels are decreased early in Marfan mice, suggesting that a defect in elastogenesis contributes to the pathology in these mice.…”

Section: Did Not Detect Enhanced Apoptosis In Intermediate Stages Of mentioning

confidence: 99%

miR-29b Participates in Early Aneurysm Development in Marfan Syndrome

Merk

Chin²,

Dake³

et al. 2012

Circulation Research

176

156

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Rationale: Marfan syndrome (MFS) is a systemic connective tissue disorder notable for the development of aortic root aneurysms and the subsequent life-threatening complications of aortic dissection and rupture. Underlying fibrillin-1 gene mutations cause increased transforming growth factor-␤ (TGF-␤) signaling. Although TGF-␤ blockade prevents aneurysms in MFS mouse models, the mechanisms through which excessive TGF-␤ causes aneurysms remain ill-defined. Objective:We investigated the role of microRNA-29b (miR-29b) in aneurysm formation in MFS. Methods and Results: Using quantitative polymerase chain reaction, we discovered that miR-29b, a microRNA regulating apoptosis and extracellular matrix synthesis/deposition genes, is increased in the ascending aorta of Marfan (Fbn1 C1039G/؉ ) mice. Increased apoptosis, assessed by increased cleaved caspase-3 and caspase-9, enhanced caspase-3 activity, and decreased levels of the antiapoptotic proteins, Mcl-1 and Bcl-2, were found in the Fbn1 C1039G/؉ aorta. Histological evidence of decreased and fragmented elastin was observed exclusively in the Fbn1 C1039G/؉ ascending aorta in association with repressed elastin mRNA and increased matrix metalloproteinase-2 expression and activity, both targets of miR-29b. Evidence of decreased activation of nuclear factor B, a repressor of miR-29b, and a factor suppressed by TGF-␤, was also observed in Fbn1 C1039G/؉ aorta. Furthermore, administration of a nuclear factor B inhibitor increased miR-29b levels, whereas TGF-␤ blockade or losartan effectively decreased miR-29b levels in Fbn1 C1039G/؉ mice. Finally, miR-29b blockade by locked nucleic acid antisense oligonucleotides prevented early aneurysm development, aortic wall apoptosis, and extracellular matrix deficiencies. Conclusions:

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Fibrillin‐1 genetic deficiency leads to pathological ageing of arteries in mice

Cited by 48 publications

References 49 publications

Microfibril-associated Glycoprotein 2 (MAGP2) Loss of Function Has Pleiotropic Effects in Vivo

Microfibril-associated Glycoprotein 2 (MAGP2) Loss of Function Has Pleiotropic Effects in Vivo

Colocalization in vivo and association in vitro of perlecan and elastin

miR-29b Participates in Early Aneurysm Development in Marfan Syndrome

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