N-Homocysteinylation impairs collagen cross-linking in cystathionine ß-synthase-deficient mice: a novel mechanism of connective tissue abnormalities.
FASEB J
; 30(11): 3810-3821, 2016 11.
Article
em En
| MEDLINE
| ID: mdl-27530978
ABSTRACT
Cystathionine ß-synthase (CBS) deficiency, a genetic disorder in homocysteine (Hcy) metabolism in humans, elevates plasma Hcy-thiolactone and leads to connective tissue abnormalities that affect the cardiovascular and skeletal systems. However, the underlying mechanism of these abnormalities is not understood. Hcy-thiolactone has the ability to form isopeptide bonds with protein lysine residues, which generates N-homocysteinylated protein. Because lysine residues are involved in collagen cross-linking, N-homocysteinylation of these lysines should impair cross-linking. Using a Tg-I278T Cbs-/- mouse model of hyperhomocysteinemia (HHcy) which replicates the connective tissue abnormalities observed in CBS-deficient patients, we found that N-Hcy-collagen was elevated in bone, tail, and heart of Cbs-/- mice, whereas pyridinoline cross-links were significantly reduced. Plasma deoxypyridinoline cross-link and cross-linked carboxyterminal telopeptide of type I collagen were also significantly reduced in the Cbs-/- mice. Lysine oxidase activity and mRNA level were not reduced by the Cbs-/- genotype. We also showed that collagen carries S-linked Hcy bound to the thiol of N-linked Hcy. In vitro experiments showed that Hcy-thiolactone modifies lysine residues in collagen type I α-1 chain. Residue K160, located in the nonhelical N-telopeptide region and involved in pyridinoline cross-link formation, was also N-homocysteinylated in vivo Taken together, our findings showed that N-homocysteinylation of collagen in Cbs-/- mice impairs its cross-linking. These findings explain, at least in part, connective tissue abnormalities observed in HHcy.-Perla-Kajan, J., Utyro, O., Rusek, M., Malinowska, A., Sitkiewicz, E., Jakubowski, H. N-Homocysteinylation impairs collagen cross-linking in cystathionine ß-synthase-deficient mice a novel mechanism of connective tissue abnormalities.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tecido Conjuntivo
/
Hiper-Homocisteinemia
/
Cistationina beta-Sintase
/
Colágeno Tipo I
/
Homocisteína
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
FASEB J
Assunto da revista:
BIOLOGIA
/
FISIOLOGIA
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Polônia