Advanced glycation end products induce apoptosis in fibroblasts through activation of ROS, MAP kinases, and the FOXO1 transcription factor

Citation:

M. Alikhani, C. M. MacLellan, M. Raptis, S. Vora, P. C. Trackman, and D. T. Graves. 2007. “Advanced glycation end products induce apoptosis in fibroblasts through activation of ROS, MAP kinases, and the FOXO1 transcription factor.” Am J Physiol Cell PhysiolAm J Physiol Cell PhysiolAm J Physiol Cell Physiol, 292, Pp. C850-6.

Abstract:

Advanced glycation end products (AGEs) are elevated in aged and diabetic individuals and are associated with pathological changes associated with both. Previously we demonstrated that the AGE N(epsilon)-(carboxymethyl)lysine (CML)-collagen induced fibroblast apoptosis through the cytoplasmic and mitochondrial pathways and the global induction of proapoptotic genes. In the present study we investigated upstream mechanisms of CML-collagen-induced apoptosis. CML-collagen induced activation of the proapoptotic transcription factor FOXO1 compared with unmodified collagen. When FOXO1 was silenced, CML-collagen-stimulated apoptosis was reduced by approximately 75% compared with fibroblasts incubated with nonsilencing small interfering RNA, demonstrating the functional significance of FOXO1 activation (P < 0.05). CML-collagen but not control collagen also induced a 3.3-fold increase in p38 and a 5.6-fold increase in JNK(1/2) activity (P < 0.05). With the use of specific inhibitors, activation of p38 and JNK was shown to play an important role in CML-collagen-induced activation of FOXO1 and caspase-3. Moreover, inhibition of p38 and JNK reduced CML-collagen-stimulated apoptosis by 48 and 57%, respectively, and by 89% when used together (P < 0.05). In contrast, inhibition of the phosphatidylinositol 3-kinase/Akt pathway enhanced FOXO1 activation. p38 and JNK stimulation by CML-collagen was almost entirely blocked when formation of ROS was inhibited and was partially reduced by NO and ceramide inhibitors. These inhibitors also reduced apoptosis to a similar extent. Together these data support a model in which AGE-induced apoptosis involves the formation of ROS, NO, and ceramide and leads to p38 and JNK MAP kinase activation, which in turn induces FOXO1 and caspase-3.

Notes:

Alikhani, ManiMaclellan, Christine MRaptis, MarkosVora, SiddarthTrackman, Philip CGraves, Dana TP01 AR-49920/AR/NIAMS NIH HHS/United StatesR01 DE-07559/DE/NIDCR NIH HHS/United StatesR01 DE-14066/DE/NIDCR NIH HHS/United StatesR01 DE007559/DE/NIDCR NIH HHS/United StatesJournal ArticleResearch Support, N.I.H., ExtramuralUnited StatesAm J Physiol Cell Physiol. 2007 Feb;292(2):C850-6. Epub 2006 Sep 27.