The Role of Endoplasmic Reticulum Stress in Fine Particulate Matter-Induced Phenotype Switching of Vascular Smooth Muscle Cells

As a major component of air pollution, fine particulate matter (PM 2.5 ) was the second global leading cause of death in 2021. Evidence from humans suggested that PM 2.5 was associated with an enhanced coronary calcium score (CAC), and animal studies indicated that PM 2.5 induced vascular calcification, while mechanisms remained largely unknown. In this study, PM 2.5 enhanced the proliferative potential and migration capacity of human aortic vascular smooth muscle cells (VSMCs), as well as disturbing intracellular Ca 2+ homeostasis. Subsequent transcriptomic analysis implicated that PM 2.5 could influence genes involved in the IRE1α-mediated unfolded protein responses and reduce the expression of DNAJB9, a co-chaperone that formed a complex with BiP/IRE1α to inhibit the activation of endoplasmic reticulum (ER) stress. Further mechanistic investigations indicated that PM 2.5 activated the IRE1α/XBP1 signaling pathway and enhanced the expression of osteogenic phenotype-related hallmarks. In contrast, pretreatment with an ER stress antagonist (4-PBA) could suppress PM 2.5 -associated calcium dysregulation and osteogenic transformation via alleviation of ER stress. Taken together, this study revealed the role of ER stress in the phenotype switching of VSMCs induced by PM 2.5, highlighted the regulation of DNAJB9, provided insights into the mechanisms of air pollution-related vascular calcification, and pointed out molecules for future investigations.