Real-ambient particulate matter exposure induced FGFR1 methylation contributes to cardiac dysfunction by altering cardiac lipid metabolism.

Particulate matter (PM)-induced cardiometabolic disorder contributes to the progression of cardiac diseases, but its epigenetic mechanisms are largely unknown. This study used bioinformatic analysis, in vivo and in vitro multiple models to investigate the role of PM-induce cardiac fibroblast growth factor 1 (FGFR1) methylation and its impact on cardiomyocyte lipid metabolic disruption. Bioinformatic analysis revealed that FGFR1 was associated with cardiac pathologies, mitochondrial function and metabolism, supporting the possibility that FGFR1 may paly regulatory roles in PM-induced cardiac functional impairment and lipid metabolism disorders. Individually ventilated cage (IVC)-based real-ambient PM exposure system mouse models were used to expose C57/BL6 mice for six and fifteen weeks. The results showed that PM induced cardiac lipid metabolism disorder, DNA nucleotide methyltransferases (DNMTs) alterations and FGFR1 expression declines in mouse heart. Lipidomics analysis revealed that carnitines, phosphoglycerides and lysophosphoglycerides were most significantly affected by PM exposure. At the cellular level, AC16 cells treated with FGFR1 inhibitor (PD173074) resulted in impaired mitochondrial and metabolic functions in cardiomyocytes. Inhibition of DNA methylation in cells by 5-AZA partially restored the FGFR1 expression, and ameliorated cardiomyocyte injury and mitochondrial functions. These changes involved alterations in AMP-activated protein kinase (AMPK)-peroxisome proliferator activated receptors γ coactivator 1α (PGC1α) pathways. Bisulfite sequencing PCR (BSP) and DNA methylation specific PCR (MSP) confirmed that PM exposure induced FGFR1 gene promoter region methylation. These results suggested that PM exposure affected cardiac injury and deranged lipid metabolism by inducing FGFR1 methylation. Overexpression of FGFR1 in mouse heart using adeno-associated virus 9 (AAV9) effectively alleviated PM-induced cardiac impairment and metabolic disorder. Our findings identified that FGFR1 methylation may be one of the potential indicators for PM-induced cardiac mitochondrial and metabolic dysfunction, providing novel insights into underlying PM-related cardiotoxic mechanisms.