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J. Biol. Chem., Vol. 280, Issue 13, 12087-12095, April 1, 2005

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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, and Dana T. Graves

From the Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, Massachusetts 02118

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--(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 .

Received for publication, June 7, 2004 , and in revised form, November 29, 2004.

^* This work was supported by National Institutes of Health Grants DE07559, DE11254, AR49920, and DE14066. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Periodontology and Oral Biology, Boston University School of Dental Medicine, 700 Albany St., Boston, MA 02118. Tel.: 617-638-8547; Fax: 617-638-4924; E-mail: dgraves{at}bu.edu.

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