Vascular calcification is a pathological process of deposition of hydroxyapatite HAp in the blood vessel, which causes stiffness and increases cardiovascular morbidity and mortality in ageing populations and in conditions such as atherosclerosis, diabetes and chronic kidney disease. It is a regulated, cell-mediated process, similar to bone formation, that involves osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs), characterised by expression of bone-specific genes in the calcified vessel. The exact mechanisms regulating this process are unknown. The endoplasmic reticulum (ER) is involved in the correct folding and secretion of proteins. ER stress occurs as a result of unfolded protein accumulation and leads to activation of a signalling pathway called the unfolded protein response (UPR), mediated by three main ER stress transducers IRE1, PERK and ATF6. ER stress has been implicated in bone development. Therefore, we hypothesised that osteogenic gene expression in VSMCs can be regulated by ER stress. Human primary VSMCs were treated with tunicamycin and thapsigargin and expression of 15 bone markers in response to ER stress was examined by Western Blotting and qPCR. SiRNA knockdowns of PERK, ATF4, ATF6 and IRE1 were performed to establish which UPR pathways are involved. ER stress was shown to downregulate expression of BMP-2 via ATF4 and ATF6. Expression of Osterix was upregulated via ATF4, PERK and IRE1. Its downstream target alkaline phosphatase was also upregulated, in an ATF-4 dependent manner. Taken together this data suggests that ER stress may play a role in VSMC osteogenic transdifferentiation via non-canonical transcriptional pathways.
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