Nanoparticle-Encapsulated 5-Azacytidine Attenuates Air Pollution-Induced Human Cardiac Fibroblast Activation

Area of Science:

• Environmental Epigenetics
• Cardiovascular Disease Research
• Nanomedicine

Background:

• Quasi-ultrafine particles (qUFPs; PM₀.₄₉) are linked to cardiovascular disease, but their epigenetic impact on human cardiac fibroblasts (HCFs) is poorly understood.
• Dysregulated DNA methylation is implicated in cardiac remodeling, yet the DNMT inhibitor 5-Azacytidine (5-Aza) has limited clinical use due to instability and toxicity.
• Nanoparticle (NP) delivery systems are being explored to enhance the stability and therapeutic efficacy of drugs like 5-Aza.

Purpose of the Study:

• To investigate the epigenetic effects of PM₀.₄₉ exposure on HCFs.
• To evaluate the efficacy of nanoparticle-delivered 5-Azacytidine (5-Aza-NP) in mitigating PM₀.₄₉-induced HCF activation and toxicity.
• To explore the potential of 5-Aza-NP as an epigenetic therapeutic strategy for PM₀.₄₉-related cardiac dysfunction.

Main Methods:

• Human cardiac fibroblasts (HCFs) were exposed to PM₀.₄₉ (low and high concentrations) collected from Thailand.
• Cells were pre-treated with free 5-Aza or 5-Aza-loaded hyaluronic acid nanoparticles (5-Aza-NP).
• Gene expression (epigenetic and pro-fibrotic markers), cell viability (MTT assay), and transcriptomic profiles (bulk RNA sequencing) were analyzed.

Main Results:

• High PM₀.₄₉ concentrations induced dysregulation of DNA methylation machinery (increased DNMT1, DNMT3A/B) and activated pro-fibrotic markers (COL1A1, α-SMA) in HCFs.
• 5-Aza treatment attenuated PM₀.₄₉-induced HCF activation and pro-fibrotic marker expression.
• 5-Aza-NP demonstrated reduced cytotoxicity and effectively mitigated PM₀.₄₉-induced HCF activation and associated transcriptomic alterations under chronic exposure.

Conclusions:

• Exposure to biomass burning-derived PM₀.₄₉ induces pathogenic HCF activation via DNA methylation dysregulation.
• 5-Aza-NP treatment attenuated PM₀.₄₉-induced fibroblast activation and modulated transcriptomic changes, suggesting a viable epigenetic therapeutic approach.
• These findings highlight the potential of 5-Aza-NP against PM₀.₄₉-induced cardiac fibroblast dysfunction, warranting further investigation with diverse PM compositions.