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Background <p>Particulate matter (PM), a mixture of solid and liquid particles suspended in the air, poses a significant environmental health risk. Exposure to PM has been linked to adverse cardiopulmonary effects, including cardiac fibrosis. Reversing the serious consequences of fibrosis or preventing its onset remains a significant challenge at present.</p> Methods <p>This project includes animal and cell-based experiments. In the animal component, C57BL/6J mice were serially exposed to PM for 3 or 6&#xa0;months. Neonatal rat cardiac fibroblasts (NRCFs) were isolated and exposed to 100&#xa0;μg/mL PM for different periods. Bafilomycin A1(BAF), compound C(CC) and siRNA were employed to explore potential pathways.</p> Results <p>Comprehensive analyses revealed that 6&#xa0;months of PM exposure in mice and 48&#xa0;h of exposure in NRCFs led to fibrosis. To explore potential preventive strategies for fibrosis caused by environmental damage, we focused on the fibroblast activation stage (3&#xa0;months in mice and 24&#xa0;h in NRCFs. Exposure to PM was found to elevate expression of hypoxia-inducible factor 1 alpha (HIF1α), activate of the AMPK–mTOR pathway and the accumulate autophagosomes both in vivo and in vitro. Treatment with the AMPK inhibitor, compound C reversed the autophagosome accumulation in PM-exposed NRCFs. Utilizing Bafilomycin A1, we demonstrated that PM blocked the fusion of autophagosomes and lysosomes (autophagy flux). Additionally, inhibiting HIF1α reduced fibroblast activation and autophagy alteration dependent on the AMPK–mTOR pathway.</p> Conclusion <p>Our findings indicate that fibroblast activation induced by PM exposure is dependent on blocked fusion of autophagosomes and lysosomes mediated by the AMPK–mTOR pathway, which is regulated by HIF1α. Targeting this pathway may provide a novel therapeutic approach for the prevention and treatment of PM-induced cardiac fibrosis.</p>

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Particulate matter induces activation of cardiac fibroblasts via HIF1α-mediated autophagy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年3月8日

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  • Zhimin Wang,
  • Guanghui Hong,
  • Runting Dou,
  • Lifeng Yan,
  • Shangheng Chen,
  • Zijie Lin,
  • Xing Ye,
  • Zhenghui Zhang,
  • Qi Shen,
  • Jianghua Du,
  • Junyi Lin,
  • Xuanyi Chen,
  • Jianhui Xie,
  • Tianyu Zhou,
  • Yiwen Shen

摘要

Background

Particulate matter (PM), a mixture of solid and liquid particles suspended in the air, poses a significant environmental health risk. Exposure to PM has been linked to adverse cardiopulmonary effects, including cardiac fibrosis. Reversing the serious consequences of fibrosis or preventing its onset remains a significant challenge at present.

Methods

This project includes animal and cell-based experiments. In the animal component, C57BL/6J mice were serially exposed to PM for 3 or 6 months. Neonatal rat cardiac fibroblasts (NRCFs) were isolated and exposed to 100 μg/mL PM for different periods. Bafilomycin A1(BAF), compound C(CC) and siRNA were employed to explore potential pathways.

Results

Comprehensive analyses revealed that 6 months of PM exposure in mice and 48 h of exposure in NRCFs led to fibrosis. To explore potential preventive strategies for fibrosis caused by environmental damage, we focused on the fibroblast activation stage (3 months in mice and 24 h in NRCFs. Exposure to PM was found to elevate expression of hypoxia-inducible factor 1 alpha (HIF1α), activate of the AMPK–mTOR pathway and the accumulate autophagosomes both in vivo and in vitro. Treatment with the AMPK inhibitor, compound C reversed the autophagosome accumulation in PM-exposed NRCFs. Utilizing Bafilomycin A1, we demonstrated that PM blocked the fusion of autophagosomes and lysosomes (autophagy flux). Additionally, inhibiting HIF1α reduced fibroblast activation and autophagy alteration dependent on the AMPK–mTOR pathway.

Conclusion

Our findings indicate that fibroblast activation induced by PM exposure is dependent on blocked fusion of autophagosomes and lysosomes mediated by the AMPK–mTOR pathway, which is regulated by HIF1α. Targeting this pathway may provide a novel therapeutic approach for the prevention and treatment of PM-induced cardiac fibrosis.