Extracellular matrix components isolated from diabetic mice alter cardiac fibroblast function through the AGE/RAGE signaling cascade

Abstract

Individuals suffering from diabetes have an increased risk of developing cardiovascular complications such as heart failure. 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 Glycation End products (AGEs) are produced and accumulate in the ECM over time in a healthy individual, but under hyperglycemic conditions, this process is accelerated. In this study, we investigated how the presence of AGEs in either non-diabetic or diabetic ECM affected fibroblast-mediated matrix remodeling. In order to address this question, diabetic and non-diabetic fibroblasts were embedded in 3D matrices composed of collagen isolated from either non-diabetic or diabetic mice. Fibroblast function was assessed using gel contraction, migration, and protein expression. 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 an "inactive" to "active" state. Addition of AGEs increase the AGE/RAGE cascade leading to increased gel contraction, whereas inhibiting the cascade resulted in little or no gel contraction. These results indicated 1) the ECM from diabetic and non-diabetic mice differ from one another, 2) diabetic ECM can impact fibroblast function and shift them toward an "active" state, and 3) that fibroblasts can modify the ECM through activation of the AGE/RAGE signaling cascade. These results suggested the importance of understanding the impact diabetes has on the ECM and fibroblast function.

Keywords: 3D extracellular matrix; AGE/RAGE signaling; Advanced glycation end products; Cardiac fibroblasts; Diabetes; Receptor for AGEs.