Decoding AGE-RAGE signal generated NF-kappaB RelA “barcode” that directs collagen I expression and impacts arterial aging

Authors

• Y Peng
• JM Kim
• HS Park
• A Yang
• C Islam
• EG Lakatta
• L Lin

Abstract

Advanced glycation end products (AGEs) accumulate in the body with advancing age, and are implicated in tissue abnormities. Although AGEs activate NF-kappaB, via the receptor (RAGE), a direct link between AGE-RAGE axis and major arterial aging phenotypes had never been established. We observed that, although both have a similar level of AGEs content, the vessels of aged RAGE-/- mice have significantly lower collagen content than that of the WT, suggesting that AGE-RAGE signaling plays a role in collagen production in the vessel. There are 4 putative NF-kappaB binding motifs within the 5’ regulatory region of col1a1 and col1a2. ChIP analysis showed that only one in each gene was bound by NF-kappaB upon AGEs stimulation, suggesting that AGEs signal results in a conditional and selective access of NF-kappaB to the 5’regulatory locus of the two genes. Cellular signals generate different post-translational modifications, or “barcode”, of RelA, resulting in different NF-kappaB transcriptional targets and dynamics. To decode AGEs signal-specific RelA “barcode”, we mutated 3 acetylation and 10 phosphorylation target residues in RelA, and tested AGEs-stimulated col1a1/col1a2 transcription in RelA-mutant reconstituted RelA-/- MEFs. While acetylation does not affect transcription of either gene, phosphorylation of RelA S311/S536 and T254/S311/S536 is required for expression of col1a1 and col1a2, respectively. Our studies provide the first clear link between AGE-RAGE signaling and arterial aging phenotype, and explains the contradictory result under TNFalpha stimulation.

Scientific Focus Area: Molecular Biology and Biochemistry

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