Advanced glycation end products enhance expression of pro-apoptotic genes and stimulate fibroblast apoptosis through cytoplasmic and mitochondrial pathways

Zoubin Alikhani, Mani Alikhani, Coy M. Boyd, Kiyoko Nagao, Philip C. Trackman, Dana T. Graves

Research output: Contribution to journalArticle

Abstract

Both aging and diabetes are characterized by the formation of advanced glycation end products (AGEs). Both exhibit other similarities including deficits in wound healing that are associated with higher rates of fibroblast apoptosis. In order to investigate a potential mechanism for enhanced fibroblast apoptosis in diabetes and aged individuals, experiments were carried out to determine whether the predominant advanced glycation end product in skin, N-ε-(carboxymethyl) lysine (CML)-collagen, could induce fibroblast apoptosis. In vivo experiments established that CML-collagen but not unmodified collagen induced fibroblast apoptosis and that apoptosis was dependent upon caspase-3, -8, and -9 activity. In vitro experiments demonstrated that CML-collagen but not control collagen induced a time- and dose-dependent increase in fibroblast apoptosis. By use of blocking antibodies, apoptosis was shown to be mediated through receptor for AGE signaling. AGE-induced apoptosis was largely dependent on the effector caspase, caspase-3, which was activated through both cytoplasmic (caspase-8-dependent) and mitochondrial (caspase-9) pathways. CML-collagen had a global effect of enhancing mRNA levels of pro-apoptotic genes that included several classes of molecules including ligands, receptors, adaptor molecules, mitochondrial proteins, and others. However, the pattern of expression was not identical to the pattern of apoptotic genes induced by tumor necrosis factor α.

Original languageEnglish (US)
Pages (from-to)12087-12095
Number of pages9
JournalJournal of Biological Chemistry
Volume280
Issue number13
DOIs
StatePublished - Apr 1 2005

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Advanced Glycosylation End Products
Fibroblasts
Genes
Apoptosis
Collagen
Caspase 8
Medical problems
Caspase 3
Effector Caspases
Molecules
Blocking Antibodies
Caspase 9
Experiments
Mitochondrial Proteins
Wound Healing
Skin
Tumor Necrosis Factor-alpha
Aging of materials
Ligands
Messenger RNA

ASJC Scopus subject areas

  • Biochemistry

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Advanced glycation end products enhance expression of pro-apoptotic genes and stimulate fibroblast apoptosis through cytoplasmic and mitochondrial pathways. / Alikhani, Zoubin; Alikhani, Mani; Boyd, Coy M.; Nagao, Kiyoko; Trackman, Philip C.; Graves, Dana T.

In: Journal of Biological Chemistry, Vol. 280, No. 13, 01.04.2005, p. 12087-12095.

Research output: Contribution to journalArticle

Alikhani, Zoubin ; Alikhani, Mani ; Boyd, Coy M. ; Nagao, Kiyoko ; Trackman, Philip C. ; Graves, Dana T. / Advanced glycation end products enhance expression of pro-apoptotic genes and stimulate fibroblast apoptosis through cytoplasmic and mitochondrial pathways. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 13. pp. 12087-12095.
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