Regulation of Lysyl Oxidase mRNA in Dermal Fibroblasts from Normal Donors and Patients with Inherited Connective Tissue Disorders

Yeowell, Heather N.; Marshall, Melanie K.; Walker, Linda C.; Ha, V.; Pinnell, Sheldon R.

doi:10.1006/abbi.1994.1042

Cited by 42 publications

(34 citation statements)

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“…Mx also stimulates LOX expression in skin fibroblasts. 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.…”

Section: Discussionsupporting

confidence: 90%

“…However, the effect of Mx on collagen synthesis seems to be species specific and cell type dependent. 8,21,[27][28][29] In our experimental conditions, the treatment of BN rats with Mx or Dx did not change the relative content (%) of collagens in the media or modify medial thickness. Moreover, Mx and Dx caused a decrease in vSMC number; this decreased aortic cellularity in Mx-treated rats was confirmed by the measurement of cell protein concentration in the 0.3% sodium dodecyl sulfate extract of each aorta.…”

Section: Discussionmentioning

confidence: 57%

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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: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 57%

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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“…Consequently, aberrant LysOX expression or enzymatic activity leads to disease. Decreases in LysOX expression or activity have been associated with such heritable connective tissue disorders as EhlerDanlos syndrome, cutis laxa, and Menkes' syndrome (Kuivaniemi et al 1985;Khakoo et al 1997;Yeowell et al 1994;Royce et al 1980;Pinnell 1982). Increases in LysOX expression contribute to the development of fibrotic diseases such as arteriosclerosis, scleroderma, and liver cirrhosis, diseases that involve connective tissue remodeling (Ooshima and Midorikawa 1977;Kagan et al 1981;Chanoki et al 1995;Kagan 1994).…”

Section: Physical and Biological Properties Of Lysoxmentioning

confidence: 99%

Lysyl oxidase: a potential target for cancer therapy

2010

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Lysyl oxidases (LysOX; EC 1.4.3.13, protein-lysine 6-oxidases) are extracellular copper enzymes that catalyze the cross-linking of collagens or elastin in the extracellular matrix (ECM), thereby regulating the tensile strength of tissues. Recent implication of LysOX in cancer, wound healing, cell motility, chemotaxis, and differentiation reflects its remarkable functional diversity and also in the central nervous system pathologies. However, recent reports also demonstrated novel roles for LysOX, including the ability to regulate gene transcription, motility/migration, and cell adhesion. These diverse functions have led researchers to hypothesize that LysOX may have multiple roles affecting both extra- and intracellular cell function(s). Both down and up-regulation of LysOX in tumor tissues and cancer cell lines have been described, suggesting a dual role for LysOX as a tumor suppressor, as well as a metastasis promoter gene. In this review we explain in detail the role of lysyl oxidase in tumor progression and metastasis.

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“…It is possible to pharmacologically affect the post-translational steps of collagen cross-linking with the lathyrogenic agent ß-aminopropionitrile (BAPN), which irreversibly inhibits lysyl oxidase (LO) by decrease of LO mRNA expression (Yeowell et al 1994). The level of the α 1 (I) collagen mRNA was not affected by BAPN.…”

mentioning

confidence: 99%

“…The level of the α 1 (I) collagen mRNA was not affected by BAPN. No significant change was observed in the steady-state level of LO mRNA in fibroblasts isolated from patients with certain genetic connective tissue disorders (Yeowell et al 1994). A substantial body of literature presents evidence on the beneficial effect of BAPN for the prevention of scar formation in humans (Peacock & Madden 1966, Keiser & Sjoerdsma 1967.…”

mentioning

confidence: 99%

Impact of Antifibrotic Treatment on the Course of Schistosoma mansoni Infection in Murine Model

Giboda¹,

Smith

1997

Mem. Inst. Oswaldo Cruz

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Regulation of Lysyl Oxidase mRNA in Dermal Fibroblasts from Normal Donors and Patients with Inherited Connective Tissue Disorders

Cited by 42 publications

References 0 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

Lysyl oxidase: a potential target for cancer therapy

Impact of Antifibrotic Treatment on the Course of Schistosoma mansoni Infection in Murine Model

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