Structure and function of the mammalian fibrillin gene family: Implications for human connective tissue diseases

Davis, Margaret R.; Summers, Kim M.

doi:10.1016/j.ymgme.2012.07.023

Cited by 92 publications

(69 citation statements)

References 118 publications

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“…21 These results are consistent with the electron microscopic observations of well-formed elastic fibers in the aorta of Mx-treated BN rats: a deficiency in one of these elastic fiber components leads to defective elastic fiber formation. [22][23][24][25] Normal elastic fiber genesis is further supported by the homogeneous increase in elastic fiber thickness observed at the histological level in Mx-and Dx-treated rats. However, the number of EL remained unchanged.…”

Section: Discussionmentioning

confidence: 69%

Potassium Channel Openers Increase Aortic Elastic Fiber Formation and Reverse the Genetically Determined Elastin Deficit in the BN Rat

et al. 2013

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H aploinsufficiency of elastin in patients with WilliamsBeuren syndrome leads, in more than half of cases, to development of supravalvular aortic stenosis and hypertension.1 Moreover, Eln +/− mice, a model for supravalvular aortic stenosis disease, have a higher arterial pressure (∆25-30 mm Hg) than their wild-type counterparts.2 These cardiovascular features are clearly linked to the decreased elastin synthesis in the aorta during development. Thus, it would be of interest to find molecules able to enhance elastin synthesis to treat this condition.We previously showed that the Brown Norway (BN) rat, a normotensive inbred strain, presents the lowest content of elastin in the aorta compared with 6 other inbred rat strains. [3][4][5] We also demonstrated that, compared with the LOU rat, the elastin deficit in the thoracic aorta of the BN rat is partly caused by a decrease in the synthesis of tropoelastin (TE), the soluble precursor of elastin. However, elastin gene polymorphism accounts for only 3.9% of the elastin content variance in F2 BNxLOU rats.4 After a genome-wide search for quantitative trait loci influencing the aortic elastin content in an F2 population derived from BN and LOU rats, we identified on chromosomes 2 and 14, 3 quantitative trait loci specifically controlling elastin levels: Ael1, Ael2, and Ael3. 6 The polymorphic marker, D2Wox26, corresponding to the maximum logarithm of odds score value of Ael2, is situated within the gene encoding for the Na + /K + -ATPase α1 subunit. In addition, several other genes encoding for potassium channels are contained in Ael1 (Kcnmb2, Hcn1) and Ael2 (Hcn3, Kcnn3, Kcnd3, Kcna2, Kcna3, and Kcna10). This result supports the hypothesis that the deficit of aortic elastin content in the BN rat could be explained by anomalies in intracellular potassium concentration ([K + ] i ).Abstract-Hypertension is a cardiovascular disorder that appears in more than half of the patients with Williams-Beuren syndrome, hemizygous for the elastin gene among 26 to 28 other genes. It was shown that the antihypertensive drug minoxidil, an ATP-dependent potassium channel opener, enhances elastic fiber formation; however, no wide clinical application was developed because of its adverse side effects. The Brown Norway rat was used here as an arterial elastin-deficient model. We tested 3 different potassium channel openers, minoxidil, diazoxide, and pinacidil, and 1 potassium channel blocker, glibenclamide, on cultured smooth muscle cells from Brown Norway rat aorta. All tested potassium channel openers increased mRNAs encoding proteins and enzymes involved in elastic fiber formation, whereas glibenclamide had the opposite effect. The higher steady-state level of tropoelastin mRNA in minoxidil-treated cells was attributable to an increase in both transcription and mRNA stability. Treatment of Brown Norway rats for 10 weeks with minoxidil or diazoxide increased elastic fiber content and decreased cell number in the aortic media, without changing collagen content. The minoxidil-induced card...

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Section: Discussionmentioning

confidence: 69%

Potassium Channel Openers Increase Aortic Elastic Fiber Formation and Reverse the Genetically Determined Elastin Deficit in the BN Rat

et al. 2013

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“…Using U0126 to increase elastin synthesis should not alter the expression of the other genes implicated in the formation of elastic fibers and thus will not lead to defective elastic fiber formation. [28][29][30][31] On the contrary, this specific effect is not deleterious to the formation of mature elastic lamellae and completely cross-linked elastin. Furthermore, because we have shown in this study, and previously, 20 …”

Section: Discussionmentioning

confidence: 98%

Inhibition of ERK1/2 Phosphorylation: A New Strategy to Stimulate Elastogenesis in the Aorta

et al. 2014

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Abstract-Haploinsufficiency of elastin leads, in more than half of patients with Williams-Beuren syndrome, to development of supravalvular aortic stenosis and hypertension. Determining mechanisms implicated in elastin synthesis would be of interest to find new elastogenic molecules to treat such a pathology. Here, we analyzed the signaling pathway linking intracellular calcium concentration to elastin regulation to find new molecules able to increase elastin synthesis. Their elastogenic ability was then investigated, in vitro and in vivo, using inhibitors of the highlighted pathway. The Brown Norway rat strain was used here as an arterial elastin-deficient model. Our data indicated that A23187, a calcium ionophore, decreases elastin expression in cultured vascular smooth muscle cells, both transcriptionally and post-transcriptionally. Addition of A23187 induced transient activation of extracellular signal-regulated kinases 1/2, leading to an upregulation of activator protein-1 transcription factors, which correlated with the inhibition of elastin gene transcription. Pretreatment with U0126, an inhibitor of extracellular signal-regulated kinases 1/2 phosphorylation, abolished the inhibition of elastin gene transcription by A23187. In vitro, U0126 increased elastin synthesis and in vivo, 24 hours after an intravenous administration, elastin gene transcription and elastin mRNA levels were increased in the rat aorta. A chronic treatment, diffusing U0126 for 10 weeks, increased aortic elastin content without changing cell number and collagen content. In conclusion, calcium ionophore represses elastin gene transcription via activation of extracellular signal-regulated kinases 1/2 pathway and activator protein-1 transcription factors. Moreover, we provide strong evidence that inhibition of extracellular signal-regulated kinases 1/2 increases elastin synthesis and could thus be suitable for treating vascular pathologies characterized by diminished arterial elastin content. (Hypertension. 2014;64:423-430.) • Online Data Supplement

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“…These proteins consist primarily of repeated epidermal growth factor (EGF) domains, most with the ability to bind calcium (Ca-EGF domains), interspersed with TB domains (reviewed by [7]; see Fig. 1 of that paper).…”

Section: Introductionmentioning

confidence: 99%

“…In mouse, Fbn1 mRNA is ubiquitous in mesenchymal cell types [10], whereas Fbn2 appears more restricted in expression ([7]; see http://biogps.org, data for Fbn2 ). A similar pattern was reported for human FBN2 [7]. Human FBN3 expression is restricted to embryonic/fetal tissues [9].…”

Section: Introductionmentioning

confidence: 99%

“…Human FBN3 expression is restricted to embryonic/fetal tissues [9]. The LTBPs are also expressed primarily in cell types of mesenchymal origin, particularly osteoblasts and chondrocytes (http://biogps.org; [7]). This restricted expression suggests that there may be common regulatory elements, permissive for expression in mesenchymal cells, in the promoter regions of the seven genes, with specific elements determining the precise cell types in which the gene is expressed.…”

Section: Introductionmentioning

confidence: 99%

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Transcriptional profiling of the human fibrillin/LTBP gene family, key regulators of mesenchymal cell functions

Davis

Andersson

Severin

et al. 2014

Molecular Genetics and Metabolism

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The fibrillins and latent transforming growth factor binding proteins (LTBPs) form a superfamily of extracellular matrix (ECM) proteins characterized by the presence of a unique domain, the 8-cysteine transforming growth factor beta (TGFβ) binding domain. These proteins are involved in the structure of the extracellular matrix and controlling the bioavailability of TGFβ family members. Genes encoding these proteins show differential expression in mesenchymal cell types which synthesize the extracellular matrix. We have investigated the promoter regions of the seven gene family members using the FANTOM5 CAGE database for human. While the protein and nucleotide sequences show considerable sequence similarity, the promoter regions were quite diverse. Most genes had a single predominant transcription start site region but LTBP1 and LTBP4 had two regions initiating different transcripts. Most of the family members were expressed in a range of mesenchymal and other cell types, often associated with use of alternative promoters or transcription start sites within a promoter in different cell types. FBN3 was the lowest expressed gene, and was found only in embryonic and fetal tissues. The different promoters for one gene were more similar to each other in expression than to promoters of the other family members. Notably expression of all 22 LTBP2 promoters was tightly correlated and quite distinct from all other family members. We located candidate enhancer regions likely to be involved in expression of the genes. Each gene was associated with a unique subset of transcription factors across multiple promoters although several motifs including MAZ, SP1, GTF2I and KLF4 showed overrepresentation across the gene family. FBN1 and FBN2, which had similar expression patterns, were regulated by different transcription factors. This study highlights the role of alternative transcription start sites in regulating the tissue specificity of closely related genes and suggests that this important class of extracellular matrix proteins is subject to subtle regulatory variations that explain the differential roles of members of this gene family.

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Structure and function of the mammalian fibrillin gene family: Implications for human connective tissue diseases

Cited by 92 publications

References 118 publications

Potassium Channel Openers Increase Aortic Elastic Fiber Formation and Reverse the Genetically Determined Elastin Deficit in the BN Rat

Potassium Channel Openers Increase Aortic Elastic Fiber Formation and Reverse the Genetically Determined Elastin Deficit in the BN Rat

Inhibition of ERK1/2 Phosphorylation: A New Strategy to Stimulate Elastogenesis in the Aorta

Transcriptional profiling of the human fibrillin/LTBP gene family, key regulators of mesenchymal cell functions

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