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Published on: February 13, 2019
PM2.5 induces cardiac defects via AHR-SIRT1-PGC-1α mediated mitochondrial damage
Jin Chen1, Mingxuan Zhang1, Stanley Aniagu2
1Suzhou medical college, Soochow University, Suzhou, China; MOE Education Key Laboratory of Geriatric Diseases and Immunology, Suzhou, China.
Abstract:
Recent evidence indicates that PM2.5 poses a risk for congenital heart diseases, but the mechanisms remain unclear. We hypothesized that AHR activated by PM2.5 might cause mitochondrial damage via PGC-1α dysregulation, leading to heart defects. We initially discovered that the PGC-1α activator ZLN005 counteracted cardiac defects in zebrafish larvae exposed to EOM (extractable organic matter) from PM2.5. Moreover, ZLN005 attenuated EOM-induced PGC-1α downregulation, mitochondrial dysfunction/biogenesis, and apoptosis. EOM exposure not only decreased PGC-1α expression levels, but suppressed its activity via deacetylation, and SIRT1 activity is required during both processes. We then found that SIRT1 expression levels and NAD+/NADH ratio were reduced in an AHR-dependent way. We also demonstrated that AHR directly suppressed the transcription of SIRT1 while promoted the transcription of TiPARP which consumed NAD+. In conclusion, our study suggests that PM2.5 induces mitochondrial damage and heart defects via AHR/SIRT1/PGC-1α signal pathway.
Insights
Particulate matter (PM2.5) exposure may cause congenital heart defects by damaging mitochondria. Our study reveals PM2.5 triggers the AHR/SIRT1/PGC-1α pathway, leading to heart abnormalities.
Area of Science:
- Environmental Health
- Cardiovascular Biology
- Mitochondrial Medicine
Background:
- Emerging evidence links fine particulate matter (PM2.5) exposure to congenital heart diseases.
- The underlying molecular mechanisms connecting PM2.5 to heart defects remain largely unknown.
- Mitochondrial dysfunction is increasingly implicated in various developmental disorders.
Purpose of the Study:
- To investigate the role of the Aryl hydrocarbon Receptor (AHR) and PGC-1α in PM2.5-induced heart defects.
- To elucidate the signaling pathway through which PM2.5 may cause cardiac abnormalities.
- To explore potential therapeutic interventions targeting mitochondrial pathways.
Main Methods:
- Utilized zebrafish larvae as a model system for PM2.5 (extractable organic matter - EOM) exposure.
- Administered ZLN005, a PGC-1α activator, to assess its protective effects.
- Analyzed PGC-1α expression and activity, mitochondrial biogenesis and function, apoptosis, SIRT1 activity, and NAD+/NADH ratios.
- Investigated the involvement of AHR in regulating SIRT1 and TiPARP expression.
Main Results:
- ZLN005 treatment counteracted EOM-induced cardiac defects in zebrafish.
- EOM exposure led to PGC-1α downregulation, impaired mitochondrial function, and increased apoptosis.
- EOM suppressed PGC-1α activity via SIRT1-dependent deacetylation.
- AHR activation by EOM reduced SIRT1 levels and NAD+/NADH ratio while increasing TiPARP transcription.
Conclusions:
- PM2.5 exposure induces mitochondrial damage and congenital heart defects through the AHR/SIRT1/PGC-1α signaling pathway.
- Targeting the AHR/SIRT1/PGC-1α axis may offer a strategy to mitigate PM2.5-related cardiovascular risks.
- This study provides novel mechanistic insights into the cardiotoxicity of air pollution.
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