PM2.5 induces cardiac defects by triggering endoplasmic reticulum stress mediated through the impairment of SIRT6 deacetylase activity

A growing body of research suggests that maternal exposure to fine particulate matter (PM2.5) is linked to congenital heart disease in the offspring. Endoplasmic reticulum stress (ERS) has been established as a cause of the cardiac developmental toxicity of PM2.5. Silent information regulator 6 (SIRT6) which serves as a protective element against environmental pollutants, was closely associated with cardiovascular conditions. However, the precise underlying molecular mechanisms remain unclear. Pregnant mice were exposed to PM2.5 or sterile saline through oropharyngeal aspiration, proteomic analysis of fetal cardiac tissue was performed. Co-immunoprecipitation analysis was used to examine the interaction of SIRT6 and PERK. We observed that maternal exposure to PM2.5 caused abnormal cardiac development in offspring, accompanied by a marked reduction in the expression of NKX2.5. In the AC16 cardiomyocyte model, exposure to PM2.5, contributed to a marked increase in cardiomyocyte apoptosis. Moreover, proteomic analysis revealed a significant disruption in protein processing in the endoplasmic reticulum. We further demonstrated that the expression of PERK and activity of the PERK/eIF2α/CHOP signaling pathway were significantly upregulated, along with a notable increase in PERK acetylation levels. More importantly, we confirmed the interaction between SIRT6 and PERK. Concurrently, a significant reduction in SIRT6 expression was detected alongside elevated H3K9 acetylation after exposure to PM2.5. The treatment of AC16 cells with the SIRT6 activator UBCS039 significantly attenuated PM2.5-induced PERK activation and cardiomyocyte apoptosis. Our results reveal that PM2.5 induces the downregulation of SIRT6, which promotes PERK hyperacetylation and activates the PERK/eIF2α/CHOP pathway, triggering ERS, ultimately resulting in abnormal cardiac development in offspring.