Extracellular Matrix Components Isolated from Diabetic Mice Alters Cardiac Fibroblast Function through the AGE/RAGE Signaling Cascade
Stephanie D. Burr and James A. Stewart, Jr.
Department of BioMolecular Sciences, The University of Mississippi, Oxford, MS
Roughly 30 million Americans suffer from diabetes and these individuals are at an increased risk of developing cardiovascular complications. A common complication is heart failure which occurs due to the stiffening of the left ventricle brought on by cardiac fibroblast “activation” that results in the remodeling 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, 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. Non-diabetic fibroblasts displayed similar matrix contraction and α-SMA expression to diabetic fibroblasts when embedded in diabetic collagen. In addition, increasing the AGE/RAGE cascade leads to increase gel contraction indicating increase in fibroblast “activation”. 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.