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AGE‐RAGE Signaling Is Intersected by Rap1a Crosstalk in Fibroblasts in Diabetic Hearts
Author(s) -
Stewart James A.,
Langford Jaslyn,
Zhao Jia,
Worsham Rebecca
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.881.4
Subject(s) - rage (emotion) , signal transduction , fibroblast , microbiology and biotechnology , endocrinology , medicine , chemistry , biology , neuroscience , biochemistry , in vitro
Rap1a is a member of the Ras GTPase superfamily that acts as a molecular switch coupling extracellular events to intracellular signaling. The purpose of this study was to identify a role for Rap1a in the AGE/RAGE signaling cascade. We hypothesized that Rap1a GTPase intersects the downstream signaling modulators of the AGE/RAGE signaling cascade to promote extracellular remodeling and fibroblast function in the diabetic heart. Initial observations demonstrated significantly elevated Rap1a protein expression levels in cardiac fibroblasts isolated from diabetic hearts. Therefore, a series of studies were performed to alter Rap1a activity and protein levels to determine the influence of Rap1a in AGE/RAGE signaling cascade. Cardiac fibroblasts were isolated from diabetic (db/db) fibroblasts and non‐diabetic (het) fibroblasts. A Rap1a‐EPAC agonist was used to increase Rap1a activity and protein levels resulting in elevated AGE/RAGE signaling markers, such as PKC‐ζ and ERK1/2 phosphorylation, α‐SMA, and RAGE protein levels. Furthermore, silencing Rap1a protein expression decreased PKC‐ζ and ERK1/2 phosphorylation, α‐SMA, and RAGE as a result of Rap1a siRNA treatment. These studies demonstrated that Rap1a crosstalk occurred in the AGE/RAGE cascade. Rap1a involvement in the AGE/RAGE cascade identifies a new molecular mechanism, which could further potentiate fibroblast differentiation and ECM remodeling in diabetes. Deactivation of this mechanism represents a potential therapeutic approach to regulate fibroblast phenotype changes, collagen accumulation, and RAGE expression. Support or Funding Information This research was supported by the American NIH Academic Research Enhancement Award (R15)(PA‐13‐313, JAS), and Department of Defense Peer Reviewed Medical Research Program ‐ Investigator‐Initiated Research Award PR150906 ‐ GRANT12018632, JAS.