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 Ca²⁺ 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.