PERK/Sestrin2 Signaling Pathway Mediated Autophagy Regulates Human Cardiomyocytes Apoptosis Induced by Traffic-Related PM and Diverse Constituents.

Although the strong causal association between PM and cardiovascular disease has been extensively studied, the latent molecular mechanisms have not been entirely explained. The objective of this research was to assess the cardiotoxicity of Traffic-related PM (TRPM), water-soluble components (WSC), and water-insoluble components (WIC) in human cardiomyocytes (AC16) and to investigate the underlying molecular mechanisms. Endoplasmic reticulum stress (ERS), autophagy, and apoptosis were activated 24 h after exposure to total-TRPM, WSC, or WIC. WIC was predominantly related to cardiotoxicity compared to WSC. Sestrin2 is an upstream molecule in several signaling pathways, including those involved in autophagy and apoptosis. In this study, we found that the knockdown of Protein Kinase RNA-like Endoplasmic Reticulum Kinase (PERK) suppressed the expression of PERK, Sestrin2, Caspase-12, Caspase-3, LC3, and p62 in TRPM-treated AC16 cells. These results indicate that ERS participates in the activation of autophagy and apoptosis through the PERK/Sestrin2 pathway. We found that inhibiting autophagy with 3-methyladenine (3-MA) decreased the expression of autophagy-related factors and aggravated apoptosis. These observations suggest that protective autophagy was initiated. Finally, our findings provide valuable insights into the molecular mechanism by which ERS might regulate autophagy through the PERK/Sestrin2 signaling pathway, and protective autophagy may be activated to relieve TRPM and component-mediated apoptosis in AC16 cells.