Mechanistic insights into PM2.5-induced cardiac fibrosis involving ERS/TXNIP/NLRP3-driven pyroptosis in multiple cell types.

Abstract

Fine particulate matter (PM_2.5) exposure leads to cardiovascular diseases (CVDs) by promoting cardiac fibrosis has been demonstrated. However, the mechanisms by which PM_2.5 induces cardiac fibrosis remain unclear. Here, we confirm that the endoplasmic reticulum stress (ERS)/thioredoxin-interacting protein (TXNIP)/nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) signaling pathway is the mechanism of action in PM_2.5-induced cardiac fibrosis, which also plays a crucial role across multiple cell types implicated in this condition. PM_2.5 exposure resulted in increased levels of reactive oxygen species (ROS), the occurrence of ERS, and upregulation of TXNIP expression, as well as pyroptosis and apoptosis in macrophages and cardiomyocytes, subsequently leading to the activation of MCF. The pyroptosis and apoptosis in macrophages and cardiomyocytes, along with MCF activation induced by PM_2.5, were significantly attenuated with the inhibitors of ERS and TXNIP. We also observed that ERS and TXNIP are involved in multiple mechanisms related to oxidative stress and the inflammatory response. We provide insights into the specific mechanisms underlying PM_2.5-induced cardiac fibrosis and suggest potential targets to control PM_2.5-induced cardiac fibrosis.