Spontaneous Right Ventricular Pseudoaneurysms and Increased Arrhythmogenicity in a Mouse Model of Marfan Syndrome

Patients with Marfan syndrome (MFS), a connective tissue disorder caused by pathogenic variants in the gene encoding the extracellular matrix protein fibrillin-1, have an increased prevalence of primary cardiomyopathy, arrhythmias, and sudden cardiac death. We have performed an in-depth in vivo and ex vivo study of the cardiac phenotype of Fbn1mgR/mgR mice, an established mouse model of MFS with a severely reduced expression of fibrillin-1. Using ultrasound measurements, we confirmed the presence of aortic dilatation and observed cardiac diastolic dysfunction in male Fbn1mgR/mgR mice. Upon post-mortem examination, we discovered that the mutant mice consistently presented myocardial lesions at the level of the right ventricular free wall, which we characterized as spontaneous pseudoaneurysms. Histological investigation demonstrated a decrease in myocardial compaction in the MFS mouse model. Furthermore, continuous 24 h electrocardiographic analysis showed a decreased heart rate variability and an increased prevalence of extrasystolic arrhythmic events in Fbn1mgR/mgR mice compared to wild-type littermates. Taken together, in this paper we document a previously unreported cardiac phenotype in the Fbn1mgR/mgR MFS mouse model and provide a detailed characterization of the cardiac dysfunction and rhythm disorders which are caused by fibrillin-1 deficiency. These findings highlight the wide spectrum of cardiac manifestations of MFS, which might have implications for patient care.

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LTBP1 promotes fibrillin incorporation into the extracellular matrix

10.1101/2021.12.16.473056 ◽

2021 ◽

Author(s):

Matthias Przyklenk ◽

Veronika Georgieva ◽

Fabian Metzen ◽

Sebastian Mostert ◽

Birgit Kobbe ◽

...

Keyword(s):

Extracellular Matrix ◽

Matrix Protein ◽

Wide Spectrum ◽

Extracellular Matrix Protein ◽

Connective Tissues ◽

Pathogenic Variants ◽

Human Pathology ◽

Fibrillin 1

LTBP1 is a large extracellular matrix protein and an associated ligand of fibrillin-microfibrils. Knowledge of LTBP1 functions is largely limited to its role in targeting and sequestering TGFβ growth factors within the extracellular matrix, thereby regulating their bioavailability. However, the recent description of a wide spectrum of phenotypes in multiple tissues in patients harboring LTBP1 pathogenic variants suggests a multifaceted role of the protein in the homeostasis of connective tissues. To better understand the human pathology caused by LTBP1 deficiency it is important to investigate its functional role in extracellular matrix formation. In this study, we show that LTBP1 coordinates the incorporation of fibrillin-1 and -2 into the extracellular matrix in vitro. We also demonstrate that this function is differentially exerted by the two isoforms, the short and long forms of LTBP1. Thereby our findings uncover a novel TGFβ-independent LTBP1 function potentially contributing to the development of connective tissue disorders.

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Genetics of vascular disease: Marfan syndrome and aortic disease

ESC CardioMed ◽

10.1093/med/9780198784906.003.0160 ◽

2018 ◽

pp. 713-715

Author(s):

Dorien Schepers ◽

Bart Loeys

Keyword(s):

Extracellular Matrix ◽

Marfan Syndrome ◽

Transforming Growth Factor Beta ◽

Matrix Protein ◽

Transforming Growth Factor ◽

Aortic Disease ◽

Extracellular Matrix Protein ◽

Genetic Defects ◽

Fibrillin 1 ◽

Growth Factor Beta

Marfan syndrome is an autosomal dominant, multisystemic disorder, presenting with skeletal, ocular, and cardiovascular symptoms. This connective tissue disease is caused by mutations in FBN1, encoding fibrillin-1, which is an important extracellular matrix protein. Marfan syndrome shows significant clinical overlap with Loeys–Dietz syndrome, which is caused by genetic defects in components of the transforming growth factor-beta pathway: TGFBR1, TGFBR2, TGFB2, TGFB3, SMAD2, and SMAD3. Overlapping clinical features between Marfan syndrome and Loeys–Dietz syndrome include aortic root aneurysm, arachnodactyly, scoliosis, and pectus deformity.

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Genetics of vascular disease: Marfan syndrome and aortic disease

ESC CardioMed ◽

10.1093/med/9780198784906.003.0160_update_001 ◽

2018 ◽

pp. 713-715

Author(s):

Dorien Schepers ◽

Bart Loeys

Keyword(s):

Extracellular Matrix ◽

Marfan Syndrome ◽

Transforming Growth Factor Beta ◽

Matrix Protein ◽

Transforming Growth Factor ◽

Aortic Disease ◽

Extracellular Matrix Protein ◽

Genetic Defects ◽

Fibrillin 1 ◽

Growth Factor Beta

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Extracellular matrix protein CCN1 induced by disturbed flow in the carotid-artery-ligation mouse model promotes neointima formation through integrin A6B1

Atherosclerosis ◽

10.1016/j.atherosclerosis.2015.04.091 ◽

2015 ◽

Vol 241 (1) ◽

pp. e22-e23

Author(s):

P.L. Hsu ◽

J.S. Chen ◽

F.E. Mo

Keyword(s):

Extracellular Matrix ◽

Carotid Artery ◽

Mouse Model ◽

Matrix Protein ◽

Extracellular Matrix Protein ◽

Neointima Formation ◽

Artery Ligation ◽

Disturbed Flow ◽

Carotid Artery Ligation

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Abstract 15539: Single-cell Analysis of Aortic Tissues From Patients With Marfan Syndrome Reveals Changes in Smooth Muscle Cell Differentiation

Circulation ◽

10.1161/circ.142.suppl_3.15539 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Ashley Dawson ◽

Yanming Li ◽

Pingping Ren ◽

Hernan Vasquez ◽

Chen Zhang ◽

...

Keyword(s):

Smooth Muscle ◽

Single Cell ◽

Marfan Syndrome ◽

Immune Cells ◽

Matrix Protein ◽

Immune Cell ◽

Aortic Aneurysms ◽

Extracellular Matrix Protein ◽

Cardiac Transplant ◽

Control Tissue

Background: Thoracic aortic aneurysms associated with Marfan syndrome (MFS) carry a high risk of mortality; however, the molecular and cellular processes leading to aortopathy in this population remain poorly understood. We aimed to use single-cell RNA (scRNA) sequencing to define the non-immune cell populations present within the aortic wall in MFS, hypothesizing that these would differ from those of non-aneurysmal control tissue. Methods: We performed scRNA sequencing of ascending aortic aneurysm tissues from MFS patients (n=3) undergoing aneurysm repair and of age-matched, non-aneurysmal control tissue from cardiac transplant donors and recipients (n=4). The Seurat package in R was used for analysis. Differentially expressed genes were identified using edgeR. Results: Eighteen non-immune cell clusters were identified, with conserved gene expression of the largest of the clusters consistent with smooth muscle cells (SMCs; n=6), fibroblasts (n=3), and endothelial cells (n=3). The SMCs and fibroblasts exhibited graded changes in their expression of contractile and extracellular matrix protein genes, supportive of a phenotypic continuum. Additionally, we identified differences in the proportions of non-immune cells in MFS tissues compared to controls. In control tissues, the most common non-immune cells expressed markers of contractile SMC maturity including CNN1 , MYH11 , and SMTN . In contrast, the largest clusters in MFS tissue were most closely related to SMCs on correlation analysis, but displayed increased expression of cyclin genes as well as immune, endothelial, and fibroblast genes indicative of de-differentiated, proliferative SMCs. Additionally, expression of genes associated with SMC phenotypic maturity, including MYH11 and MYOCD , were significantly downregulated in several of the MFS SMC clusters. Conclusion: Our data demonstrate a phenotypic continuum between fibroblasts and SMCs, with aortas from patients with MFS exhibiting an increased proportion of de-differentiated, proliferative SMCs compared to controls. Additionally, markers of SMC maturity were downregulated in SMCs in MFS compared to controls. This may be due to disruption of signaling pathways that promote differentiation.

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The iron-regulated surface determinant B (IsdB) protein from Staphylococcus aureus acts as a receptor for the host protein vitronectin

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.013510 ◽

2020 ◽

Vol 295 (29) ◽

pp. 10008-10022 ◽

Cited By ~ 2

Author(s):

Giampiero Pietrocola ◽

Angelica Pellegrini ◽

Mariangela J. Alfeo ◽

Loredana Marchese ◽

Timothy J. Foster ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Extracellular Matrix ◽

Matrix Protein ◽

Wide Spectrum ◽

Surface Proteins ◽

Host Protein ◽

Extracellular Matrix Protein ◽

Bacterial Cells ◽

Iron Starvation ◽

Extracellular Matrix Components

Staphylococcus aureus is an important bacterial pathogen that can cause a wide spectrum of diseases in humans and other animals. S. aureus expresses a variety of virulence factors that promote infection with this pathogen. These include cell-surface proteins that mediate adherence of the bacterial cells to host extracellular matrix components, such as fibronectin and fibrinogen. Here, using immunoblotting, ELISA, and surface plasmon resonance analysis, we report that the iron-regulated surface determinant B (IsdB) protein, besides being involved in heme transport, plays a novel role as a receptor for the plasma and extracellular matrix protein vitronectin (Vn). Vn-binding activity was expressed by staphylococcal strains grown under iron starvation conditions when Isd proteins are expressed. Recombinant IsdB bound Vn dose dependently and specifically. Both near-iron transporter motifs NEAT1 and NEAT2 of IsdB individually bound Vn in a saturable manner, with KD values in the range of 16–18 nm. Binding of Vn to IsdB was specifically blocked by heparin and reduced at high ionic strength. Furthermore, IsdB-expressing bacterial cells bound significantly higher amounts of Vn from human plasma than did an isdB mutant. Adherence to and invasion of epithelial and endothelial cells by IsdB-expressing S. aureus cells was promoted by Vn, and an αvβ3 integrin-blocking mAb or cilengitide inhibited adherence and invasion by staphylococci, suggesting that Vn acts as a bridge between IsdB and host αvβ3 integrin.

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Effect of beta-blocker therapy on progression of aortic dilatation in the Marfan syndrome patients with subtypes of fibrillin 1 gene mutation

Archives of Cardiovascular Diseases Supplements ◽

10.1016/j.acvdsp.2018.10.289 ◽

2019 ◽

Vol 11 (1) ◽

pp. 131

Author(s):

N. Kim ◽

J. Plaisancie ◽

T. Edouard ◽

M. Ratsimandresy ◽

P. Acar ◽

...

Keyword(s):

Gene Mutation ◽

Marfan Syndrome ◽

Beta Blocker ◽

Aortic Dilatation ◽

Blocker Therapy ◽

Beta Blocker Therapy ◽

Fibrillin 1

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Integrin-αvβ3 regulates thrombopoietin-mediated maintenance of hematopoietic stem cells

Blood ◽

10.1182/blood-2011-02-335430 ◽

2012 ◽

Vol 119 (1) ◽

pp. 83-94 ◽

Cited By ~ 45

Author(s):

Terumasa Umemoto ◽

Masayuki Yamato ◽

Jun Ishihara ◽

Yoshiko Shiratsuchi ◽

Mika Utsumi ◽

...

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

Matrix Protein ◽

Ex Vivo ◽

Extracellular Matrix Protein ◽

Αvβ3 Integrin ◽

Hematopoietic Stem ◽

Β3 Integrin ◽

Ex Vivo Culture

AbstractThroughout life, one's blood supply depends on sustained division of hematopoietic stem cells (HSCs) for self-renewal and differentiation. Within the bone marrow microenvironment, an adhesion-dependent or -independent niche system regulates HSC function. Here we show that a novel adhesion-dependent mechanism via integrin-β3 signaling contributes to HSC maintenance. Specific ligation of β3-integrin on HSCs using an antibody or extracellular matrix protein prevented loss of long-term repopulating (LTR) activity during ex vivo culture. The actions required activation of αvβ3-integrin “inside-out” signaling, which is dependent on thrombopoietin (TPO), an essential cytokine for activation of dormant HSCs. Subsequent “outside-in” signaling via phosphorylation of Tyr747 in the β3-subunit cytoplasmic domain was indispensable for TPO-dependent, but not stem cell factor-dependent, LTR activity in HSCs in vivo. This was accompanied with enhanced expression of Vps72, Mll1, and Runx1, 3 factors known to be critical for maintaining HSC activity. Thus, our findings demonstrate a mechanistic link between β3-integrin and TPO in HSCs, which may contribute to maintenance of LTR activity in vivo as well as during ex vivo culture.

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