Gestational exposure to PM2.5 impaired cardiac development through ANGPTL4-mediated mitochondrial metabolic dysfunction.

INTRODUCTION

Increasing epidemiological studies suggested that maternal exposure to fine particulate matter (PM2.5) was associated with congenital heart defects (CHD) in fetuses, while the exact mechanisms were still unclear.

OBJECTIVE

This study aimed to investigate PM2.5-induced effects on cardiac development and elucidate the implicated mechanisms.

METHODS AND

RESULTS

In the present study, we first identified that angiopoietin-like 4 (ANGPTL4), sirtuin 3 (SIRT3), and D2-hydroxyglutarate (D2-HG) may be potential biomarkers for PM2.5-related cardiac defects in human umbilical cord serum samples. Moreover, in utero exposure to PM2.5 resulted in increased left ventricular wall thickness, mitochondrial dysfunction, and metabolic changes in the hearts of the offspring mice, while knockout of ANGPTL4 could attenuate PM2.5-induced pathological changes. Furthermore, in vitro investigations revealed that ANGPTL4 may directly bind to a mitochondria-located deacetylase SIRT3 and inhibit its deacetylation capacity. Reduced SIRT3 subsequently enhanced the acetylation of lon peptidase 1 (LONP1), a quality-control protease that was indispensable in maintaining mitochondrial function. More importantly, mitochondrial dysfunction caused by loss of LONP1 further reduced the expression of D2-hydroxyglutarate dehydrogenase (D2HGDH), which disrupted the conversion of D2HG to α-ketoglutarate (α-KG) and impeded energy generation in mitochondria.

CONCLUSION

These findings suggested that PM2.5 may impair cardiac development through ANGPTL4-mediated mitochondrial dysfunction, which provided a mechanistic basis for further investigation and prevention of PM2.5-related birth defects.