Ultrastructure of Aortic Elastic Fibers in Copper-Deficient Sika Deer(Cervus nippon Temminck).

Yoshikawa, Haruhisa; Wang, Shueqin; Seo, Hirokazu; Kurotaki, Tetsuro; Ueki, Hideaki; Yoshikawa, Takashi

doi:10.1292/jvms.63.163

Cited by 4 publications

(6 citation statements)

References 22 publications

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“…In the rofecoxib-treated group, the elastic lamellae in the tunica media of the thoracic aorta were focally disrupted, resulting in a greater degree of branching than those in the control aorta. These observations are similar to the findings in animals and humans under conditions inhibiting cross-linking of elastin fibers (Herd and Orbison, 1966;Andrews et al, 1975;Hashimoto et al, 1981;Light et al, 1986;Yoshikawa et al, 2001). In our previous report (Oitate et al, 2006), we demonstrated that the radioactivity from [ 14 C]rofecoxib was localized on the elastic fibers of rat aortas by microautoradiography and that the accumulation of radioactivity in the aortas increased in a dosefrequency-dependent manner.…”

Section: Discussionsupporting

confidence: 87%

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Mechanism for Covalent Binding of Rofecoxib to Elastin of Rat Aorta

Oitate¹,

Hirota²,

Takahashi³

et al. 2006

J Pharmacol Exp Ther

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We have previously reported that oral administration of [14 C]rofecoxib to rats resulted in the long retention of radioactivity by the aorta as a consequence of covalent binding to elastin. Treatment of rats with ␣-phenyl-␣-propylbenzeneacetic acid 2-[diethylamino]-ethyl ester hydrochloride (SKF-525A), a cytochrome P450 inhibitor, significantly decreased the systemic exposure of 5-hydroxyrofecoxib, one of the main metabolites of rofecoxib, whereas there was no statistically significant change in the retention of radioactivity from [14 C]rofecoxib in the aorta. On the other hand, the aortic retention of radioactivity closely correlated to the systemic exposure of unchanged rofecoxib in the dose range between 2 and 10 mg/kg. A covalent binding study of [14 C]rofecoxib in vitro using rat aorta homogenate in the presence of D-penicillamine, hydralazine, ␤-aminopropionitrile, and sodium borohydride suggested that the aldehyde group of allysine in elastin was relevant to the covalent binding. In a model reaction using benzaldehyde, rofecoxib but not 5-hydroxyrofecoxib reacted with the aldehyde group of benzaldehyde in a manner of condensation reaction under a physiological pH condition. A histopathological examination using an electron microscope demonstrated that multiple oral administration of rofecoxib to rats caused marked degradation of the elastic fiber system of the aorta. These results suggested that rofecoxib as such is reactive in vivo, undergoing a condensation reaction with allysine, thereby preventing the formation of cross-linkages in elastin, i.e., desmosine and isodesmosine, and causing the degradation of the elastic fibers.

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Section: Discussionsupporting

confidence: 87%

“…7A). It has been demonstrated that the prevention of this cross-linking in elastin causes serious lesions of connective tissues in animals and humans (Herd and Orbison, 1966;Andrews et al, 1975;Hashimoto et al, 1981;Junker et al, 1982;Light et al, 1986;Yoshikawa et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Mechanism for Covalent Binding of Rofecoxib to Elastin of Rat Aorta

Oitate¹,

Hirota²,

Takahashi³

et al. 2006

J Pharmacol Exp Ther

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“…DISCUSSION LOX initiates the formation of the lysine-derived crosslinks in tropoelastin, resulting in the mechanical stability of elastic fibers. A deficiency in enzyme activity of LOX resulting from treatment with BAPN, 20) copper deficient 21) or genetic modification 12) leads to aortic aneurysms and cardiovascular dysfunction. Previously, we and others found that inhibition of LOX enzyme activity by BAPN leads to loss-of-elastin assembly.…”

Section: )mentioning

confidence: 99%

Lysyl Oxidase Enhances the Deposition of Tropoelastin through the Catalysis of Tropoelastin Molecules on the Cell Surface

Sato

Seino-Sudo

Okada

et al. 2017

Biological & Pharmaceutical Bulletin

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The cross-linking of elastin by lysyl oxidase (LOX) family members is essential for the integrity and elasticity of elastic fibers, which play an important role in the characteristic resilience of various tissues. However, the temporal sequence of oxidation by LOX during elastic fiber formation is still incompletely understood. Here, we demonstrate that the cross-linking of tropoelastin molecules by LOX occurs concurrent with elastin deposition. Our data show that LOX deficiency or the inhibition of LOX enzyme activity leads to the loss of elastin deposition in skin fibroblast. Moreover, overexpression of LOX promotes the deposition and alignment of tropoelastin, whereas the addition of recombinant active-form of LOX in culture medium caused abnormal elastic fiber assembly. Immunoblotting and immunofluorescence show that LOX and tropoelastin are present together with fibronectin on the cell surface of preconfluent cultures. Further, fluorescence activated cell sorting (FACS) analysis for the localization of LOX on the cell surface reveals that the transfer of LOX to the extracellular space occurs in association with elastic fiber formation. In conclusion, our results support the view that LOX and tropoelastin are present on the cell surface and suggests the possibility that lysine oxidation by LOX precedes tropoelastin deposition onto microfibrils.Key words lysyl oxidase; elastic fiber; tropoelastin Elastic fibers are major insoluble extracellular matrix structures that impart elasticity to organs such as skin, lung, ligament and arteries. Elastin assembly into a fibrillar matrix is believed to be a complex stepwise process. In the first step, secreted soluble monomeric elastin molecules (called tropoelastin) self-aggregate thorough coacervation, a process that concentrates and aligns tropoelastin molecules for cross-linking. Tropoelastin aggregates are then deposited onto preformed microfibrillar templates, which act as a molecular scaffold. Finally, the oxidative deamination of peptidyl lysine residues in tropoelastin is catalyzed by lysyl oxidase (LOX) to form mature elastic fibers. However, the precise mechanism of elastic fiber assembly remains unknown.Self-aggregation of tropoelastin through coacervation plays an important role in the alignment of tropoelastin monomers for polymeric assembly and cross-link formation.1,2) Hydrophobic domains of tropoelastin are rich in amino acids such as glycine, proline, valine and leucine, which are present in a variety of tandem repeat sequence, i.e., VGVAPG and GGLG(V/A). The tandem repeat sequences aggregate via β-sheet/β-turn structure 3,4) and thereby contribute to the polymerization of tropoelastin. 5,6) We have found that exons 16 and 30, which encode hydrophobic domains containing tandem repeat sequences, are important for the assembly process.5,7) The absence of these exons results in a failure of elastin to polymerize on microfibrils.During coacervation, tropoelastin molecules organize into small spheres and the addition of lysyl oxidase facilitates crosslink o...

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“…10,15 Similar structural changes have been observed in wild ruminants. 27 The histopathologic changes observed in human aortic aneurysms comprise elastic fiber fragmentation, accumulation of ground substance, loss of smooth muscle cells, and fibrosis within the arterial media. 13,22 Historically, these histologic features have been considered aneurysm specific, but further investigations revealed the occurrence of morphologically identical changes in the normal aging human aorta, albeit to a lesser extent compared with those described in aneurysms.…”

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confidence: 99%

Persistent Truncus Arteriosus with Dissecting Aneurysm and Subsequent Cardiac Tamponade in a Lamb

2009

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Abstract. The present case report describes the necropsy and histopathology findings of a 3-week-old lamb with persistent truncus arteriosus (PTA). This rare cardiac malformation was characterized by the presence of a common arterial trunk arising from the right ventricle and overriding a ventricular septal defect. The pulmonary arteries originated from a short common trunk from this PTA, which subsequently continued as the thoracic aorta. The death of the lamb was attributed to a rupture of the PTA with subsequent cardiac tamponade. Histologically, a dissecting aneurysm with elastic fiber fragmentation in the wall of the PTA was identified as the underlying pathologic condition. Altered hemodynamic forces with subsequent secondary vasculopathy, as well as congenital primary vasculopathies, should be considered as an underlying pathogenetic mechanism.

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Ultrastructure of Aortic Elastic Fibers in Copper-Deficient Sika Deer(Cervus nippon Temminck).

Cited by 4 publications

References 22 publications

Mechanism for Covalent Binding of Rofecoxib to Elastin of Rat Aorta

Mechanism for Covalent Binding of Rofecoxib to Elastin of Rat Aorta

Lysyl Oxidase Enhances the Deposition of Tropoelastin through the Catalysis of Tropoelastin Molecules on the Cell Surface

Persistent Truncus Arteriosus with Dissecting Aneurysm and Subsequent Cardiac Tamponade in a Lamb

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