Abstract
The Advanced Glycation End-Products (AGE)/Receptor for AGEs (RAGE) signaling pathway exacerbates diabetes-mediated vascular calcification (VC) in vascular smooth muscle cells (VSMCs). Other cell types are involved in VC, such as adventitial fibroblasts (AFBs). We hope to elucidate some of the mechanisms responsible for differential signaling in diabetes-mediated VC with this work. This work utilizes RAGE knockout animals and in vitro calcification to measure calcification and protein responses. Our calcification data revealed that VSMCs calcification was AGE/RAGE dependent, yet AFBs calcification was not an AGE-mediated RAGE response. Protein expression data showed VSMCs lost their phenotype marker, α-smooth muscle actin, and had a higher RAGE expression over non-diabetics. RAGE knockout (RKO) VSMCs did not show changes in phenotype markers. P38 MAPK, a downstream RAGE-associated signaling molecule, had significantly increased activation with calcification in both diabetic and diabetic RKO VSMCs. AFBs showed a loss in myofibroblast marker, α-SMA, due to calcification treatment. RAGE expression decreased in calcified diabetic AFBs, and P38 MAPK activation significantly increased in diabetic and diabetic RKO AFBs. These findings point to potentially an alternate receptor mediating the calcification response in the absence of RAGE. Overall, VSMCs and AFBs respond differently to calcification and the application of AGEs.
Highlights
34.2 million Americans live with type 2 diabetes mellitus (T2DM) (Centers for Disease Control and Prvention, 2020)
The loss of receptor for advanced glycation end products (RAGE) in both non-diabetic and diabetic RAGE knockout (RKO) vascular smooth muscle cells (VSMC) exhibited no changes in calcification, and with the addition of advanced glycation end-products (AGEs), calcification levels did not change (Figures 1A–C)
In in vivo physiological conditions, VSMCs and adventitial fibroblasts (AFBs) experience a very similar microenvironment. These two cell types reside in different vessel layers, but imbalances in minerals and hyperglycemia are still present throughout the vessel architecture
Summary
34.2 million Americans live with type 2 diabetes mellitus (T2DM) (Centers for Disease Control and Prvention, 2020). Diabetic patients exhibit mineral imbalances, such as hyperphosphatemia and hypercalcemia (Yamaguchi et al, 2011; Wang and Wei, 2017). Placing these patients at a higher risk for cardiovascular disease and stroke (Chonchol et al, 2009; McGurnaghan et al, 2019). VC resulted from the deposition of hydroxyapatite minerals and was characterized by a phenotypic switch of VSMCs to osteoblastlike cells (Steitz et al, 2001; Rzucidlo et al, 2007; Chang et al, 2008). When hyperglycemia and hyperphosphatemia are combined, VC was accelerated as demonstrated by Wang et al (2019)
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