AGE-RAGE signal generates a specific NF-κB RelA barcode that directs collagen I expression

Advanced glycation end products (AGEs) are sugar-modified biomolecules that accumulate in the body with advancing age, and are implicated in the development of multiple age-associated structural and functional abnormities and diseases. It has been well documented that AGEs signal via their receptor RAGE to activate several cellular programs including NF-kappa B, leading to inflammation. A large number of stimuli can activate NF-kappa B; yet different stimuli, or the same stimulus for NF-kappa B in different cellular settings, produce a very different transcriptional landscape and physiological outcome. The NF-kappa B barcode hypothesis posits that cellular network dynamics generate signal-specific post-translational modifications, or a barcode to NF-kappa B, and that a signature barcode mediates a specific gene expression pattern. In the current study, we established that AGE-RAGE signaling results in NF-kappa B activation that directs collagen Ia1 and Ia2 expression. We further demonstrated that AGE-RAGE signal induces phosphorylation of RelA at three specific residues, T254, S311, and S536. These modifications are required for transcription of collagen I genes and are a consequence of cellular network dynamics. The increase of collagen content is a hallmark of arterial aging, and our work provides a potential mechanistic link between RAGE signaling, NF-kappa B activation, and aging-associated arterial alterations in structure and function.