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Extracellular matrix components isolated from diabetic mice alters cardiac fibroblast function through the AGE/RAGE signaling cascade
Author(s) -
Burr Stephanie,
Stewart James A
Publication year - 2019
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.2019.33.1_supplement.530.1
Subject(s) - extracellular matrix , fibroblast , rage (emotion) , endocrinology , medicine , signal transduction , microbiology and biotechnology , chemistry , biology , in vitro , neuroscience , biochemistry
Roughly 30 million Americans suffer from diabetes and these individuals are at an increased risk of developing cardiovascular complications. The most common type of cardiovascular complication is heart failure, where the heart is unable to adequately pump blood throughout the body. Heart failure can be a result of the stiffening of the left ventricle which occurs when cardiac fibroblasts become “active” and begin to remodel the extracellular matrix (ECM). Fibroblast “activation” can be triggered by the AGE/RAGE signaling cascade. Advanced Glycated End products (AGEs) are produced and accumulate in the ECM overtime in a healthy individual, but under hyperglycemic conditions, this process is accelerated. We aim to investigate how the presence of AGEs in the either diabetic or non‐diabetic ECM can affect fibroblast ECM remodeling as well as determine the role of AGE/RAGE signaling during this process. In order to assess this question diabetic and non‐diabetic fibroblasts were embedded in 3D matrices composed of collagen isolated from either diabetic or non‐diabetic mice. Fibroblast function was assessed using gel contraction, migration, proliferation, and protein expression. The role of AGE/RAGE signaling during the 3D matrix experiment was determined by either activating the signaling pathway using AGE‐BSA or inhibiting specific signaling components through drug treatments. Non‐diabetic fibroblasts displayed similar gel contraction to diabetic cells when embedded in diabetic collagen. Thus, suggesting the diabetic ECM can alter fibroblast function from “inactive” to “active” states. In addition, increasing the AGE/RAGE cascade leads to increase gel contraction whereas inhibiting the cascade leads to little or no gel contraction. These results indicate 1) the ECM from diabetic and non‐diabetic mice differ from one another, 2) diabetic ECM can impact fibroblast function and shift them towards an “active” state, and 3) that fibroblasts can modify the ECM through activation of the AGE/RAGE signaling cascade. These results suggest the importance of understanding the impact diabetes has on the ECM and fibroblast function, more specially how these two components are intertwined with one another. Unraveling this issue will provide better insight into the impact of diabetic and cardiovascular complications. Support or Funding Information US Army Medical Research Award #81XWH‐16‐1‐0710 University of Mississippi School of Pharmacy; Department of BioMolecular Sciences This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .