Dept. of BioMolecular Sciences, School of Pharmacy, University of Mississippi, Oxford, MS 38677, United States of America.
Life Sci. 2020 Jun 1;250:117569. doi: 10.1016/j.lfs.2020.117569. Epub 2020 Mar 19.
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.
患有糖尿病的个体患心血管并发症（如心力衰竭）的风险增加。心力衰竭可能是左心室僵硬的结果，当心肌成纤维细胞变得“活跃”并开始重塑细胞外基质（ECM）时，就会发生这种情况。成纤维细胞的“激活”可能是由 AGE/RAGE 信号级联触发的。在健康个体中，随着时间的推移，高级糖基化终产物（AGEs）会在 ECM 中产生并积累，但在高血糖条件下，这一过程会加速。在这项研究中，我们研究了 AGEs 在非糖尿病或糖尿病 ECM 中的存在如何影响成纤维细胞介导的基质重塑。为了解决这个问题，将糖尿病和非糖尿病成纤维细胞嵌入由来自非糖尿病或糖尿病小鼠的胶原蛋白组成的 3D 基质中。通过凝胶收缩、迁移和蛋白质表达评估成纤维细胞的功能。当嵌入糖尿病胶原蛋白中时，非糖尿病成纤维细胞显示出与糖尿病细胞相似的凝胶收缩。因此，这表明糖尿病 ECM 可以将成纤维细胞的功能从“不活跃”转变为“活跃”状态。AGEs 的添加增加了 AGE/RAGE 级联反应，导致凝胶收缩增加，而抑制级联反应则导致凝胶收缩很少或没有。这些结果表明：1）来自糖尿病和非糖尿病小鼠的 ECM 彼此不同；2）糖尿病 ECM 可以影响成纤维细胞的功能并使其向“活跃”状态转变；3）成纤维细胞可以通过激活 AGE/RAGE 信号级联来修饰 ECM。这些结果表明，了解糖尿病对 ECM 和成纤维细胞功能的影响非常重要。
