Comparison of the effects of semicarbazide and β-aminopropionitrile on the arterial extracellular matrix in the Brown Norway rat

Mercier, Nathalie; Kakou, Augustine; Challande, Pascal; Lacolley, Patrick; Osborne-Pellegrin, Mary

doi:10.1016/j.taap.2009.06.005

Cited by 34 publications

(31 citation statements)

References 46 publications

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“…This BAPN effect is in accord with previous reports in the Wistar (28) and the BN rat (7, 22). Lysyl oxidase, which is inhibited by BAPN, catalyzes the formation of cross-links in elastin and collagen fibers and plays a critical role in maintaining homeostasis of the elastic lamina (8).…”

Section: Discussionsupporting

confidence: 93%

“…Male subcongenic rats were treated from the age of 5 wk by a daily intraperitoneal injection of 0.2 ml per 100 g body weight of BAPN solution, corresponding to a dose of 100 mg/kg/day of BAPN free base. This dose has been used in previous studies (22, 28) and has been shown to affect arterial RIEL without having any general toxic effects. The treatment was stopped at 12 wk of age and rats were phenotyped at 14–16 wk of age.…”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, IEL defects have been anticipated by various authors as initiator lesions of atherosclerosis in humans (9, 20) and reported to be so in ApoE-KO mice (16). Although it appears to be primarily a genetically determined characteristic, RIEL formation in the BN AA can be increased by the administration during the period of rapid growth of the lysyl oxidase inhibitors, β-aminopropionitrile (BAPN) and semicarbazide, and BAPN can even induce their formation before they appear spontaneously (7, 22). This observation led us to suspect the implication of a gene involved in elastin cross-linking.…”

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confidence: 99%

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Protease inhibitor 15, a candidate gene for abdominal aortic internal elastic lamina ruptures in the rat

Falak

Schäfer

Baud

et al. 2014

Physiological Genomics

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The inbred Brown Norway (BN) rat develops spontaneous ruptures of the internal elastic lamina (RIEL) of the abdominal aorta (AA) and iliac arteries. Prior studies with crosses of the BN/Orl RJ (susceptible) and LOU/M (resistant) showed the presence of a significant QTL on chromosome 5 and the production of congenic rats proved the involvement of this locus. In this study, we further dissected the above-mentioned QTL by creating a new panel of LOU.BN(chr5) congenic and subcongenic lines and reduced the locus to 5.2 Mb. Then we studied 1,002 heterogeneous stock (HS) rats, whose phenotyping revealed a low prevalence and high variability for RIEL. High-resolution mapping in the HS panel detected the major locus on chromosome 5 (log P > 35) and refined it to 1.4 Mb. Subsequently, RNA-seq analysis on AA of BN, congenics, and LOU revealed expression differences for only protease inhibitor 15 (Pi15) gene and a putative long intergenic noncoding RNA (lincRNA) within the linkage region. The high abundance of lincRNA with respect to reduced Pi15 expression, in conjunction with exertion of longitudinal strain, may be related to RIEL, indicating the potential importance of proteases in biological processes related to defective aortic internal elastic lamina structure. Similar mechanisms may be involved in aneurysm initiation in the human AA.

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Section: Discussionsupporting

confidence: 93%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Protease inhibitor 15, a candidate gene for abdominal aortic internal elastic lamina ruptures in the rat

Falak

Schäfer

Baud

et al. 2014

Physiological Genomics

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“…In the same report, Yu and colleagues demonstrated that FPFA was able to inhibit both SSAO and monoamine oxidases (MAO). More recently, by performing pharmacological research on arterial thickness alteration, Mercier and colleagues repeatedly administrated the reference inhibitor of SSAO, namely, semicarbazide, at 100 mg/kg bw/d to Sprague-Dawley [2], and Brown-Norway rats [3]. In both models, the authors observed a dramatically reduced body weight gain in response to the SSAO inhibitor, which also induced a decrease in the pressure resistance of arteries, as initially expected.…”

Section: Introductionmentioning

confidence: 83%

Oral Administration of Semicarbazide Limits Weight Gain together with Inhibition of Fat Deposition and of Primary Amine Oxidase Activity in Adipose Tissue

Mercader

Iffiú-Soltész²,

Bour³

et al. 2011

Journal of Obesity

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An enzyme hitherto named semicarbazide-sensitive amine oxidase (SSAO), involved in the oxidation of primary amines, is abundantly expressed in adipocytes. Although SSAO physiological functions remain unclear, several molecules inhibiting its activity have been described to limit fat accumulation in preadipocyte cultures or to reduce body weight gain in obese rodents. Here, we studied whether oral administration of semicarbazide, a prototypical SSAO inhibitor, limits fat deposition in mice. Prolonged treatment with semicarbazide at 0.125% in drinking water limited food and water consumption, hampered weight gain, and deeply impaired fat deposition. The adiposomatic index was reduced by 31%, while body mass was reduced by 15%. Such treatment completely inhibited SSAO, but did not alter MAO activity in white adipose tissue. Consequently, the insulin-like action of the SSAO substrate benzylamine on glucose transport was abolished in adipocytes from semicarbazide-drinking mice, while their insulin sensitivity was not altered. Although semicarbazide is currently considered as a food contaminant with deleterious effects, the SSAO inhibition it induces appears as a novel concept to modulate adipose tissue development, which is promising for antiobesity drug discovery.

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“…LOX enzyme inhibitors such as BAPN have been reported to modulate vessel lumen narrowing in a rabbit balloon angioplasty model [14]. Other authors using LOX inhibitors have reported, in a model of Brown Norway rats, decreased carotid wall rupture, decreased aortic insoluble elastin and increased defects in the internal elastic lamina of different arteries [15]. …”

Section: Discussionmentioning

confidence: 99%

Role of Lysyl Oxidases in Neointima Development in Vascular Allografts

Rodríguez

Pascual²,

Cifuentes³

et al. 2010

J Vasc Res

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Background: Extracellular matrix deposition is the main factor inducing stenotic lesions in arterial grafts. Lysyl oxidases (LOX) play a key role in stabilizing collagen and elastin. Objective: To examine the repair response to arterial allografts in terms of LOX expression and collagen/elastin deposition using LOX inhibitors. Methods: Lewis/Fisher-344 rats were used as donors/recipients. Donor segments were grafted to the right iliac artery of recipients and retrieved 14/30 (short-term) or 90/180 days (long-term) after surgery. One group of animals was injected with a potent irreversible LOX inhibitor daily for 30 days. Results: Intimal hyperplasia increased in thickness until 90/180 days postsurgery. Elastin showed great expression in the neointima at 14/30 days and in the media at 90/180 days. LOX/LOXL1 were similarly expressed in the arterial wall during the first month. In the long term, their overexpression was confined to neointimal layers. At 14 days, collagen types I/III were identified in the grafts. The neointima acquired collagen I over time. In the group of animal treated with the LOX inhibitor, intimal hyperplasia was significantly inhibited. Conclusion: LOX were overexpressed in late stages of intimal hyperplasia in the allografts. LOX inhibitors prevented the development of the neointimal layer, such that their modulation could reduce the excessive extracellular matrix deposition that leads to stenosis.

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Comparison of the effects of semicarbazide and β-aminopropionitrile on the arterial extracellular matrix in the Brown Norway rat

Cited by 34 publications

References 46 publications

Protease inhibitor 15, a candidate gene for abdominal aortic internal elastic lamina ruptures in the rat

Protease inhibitor 15, a candidate gene for abdominal aortic internal elastic lamina ruptures in the rat

Oral Administration of Semicarbazide Limits Weight Gain together with Inhibition of Fat Deposition and of Primary Amine Oxidase Activity in Adipose Tissue

Role of Lysyl Oxidases in Neointima Development in Vascular Allografts

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