Cardiovasc Toxicol. 2026 Jul 16;26(8):82. doi: 10.1007/s12012-026-10161-4.
ABSTRACT
Quasi-ultrafine particles (qUFPs; particulate matter < 0.49 μm; PM0.49) exposure is a key environmental contributor to cardiovascular disease, but its epigenetic impact on human cardiac fibroblasts (HCFs) remains unclear. Dysregulated DNMT activity and aberrant DNA methylation have been implicated in fibroblast activation and cardiac remodelling; however, the clinical utility of the DNMT inhibitor 5-Azacytidine (5-Aza) remains limited by chemical instability and toxicity, motivating nanoparticle (NP)-based delivery to improve stability and sustain therapeutic exposure. PM0.49 was collected from Chiang Dao district, Chiang Mai Province, Thailand. HCFs were exposed to PM0.49 (low and high concentrations), with or without pre-treatment using free 5-Aza or 5-Aza-loaded hyaluronic acid nanoparticles (5-Aza-NP). Epigenetic and pro-fibrotic gene markers were quantified using RT‑qPCR, and cell viability was assessed by MTT assay. Additionally, transcriptomic analysis using bulk RNA sequencing was performed to evaluate the effects of PM0.49 on HCFs and their modulation by 5-Aza-NP treatment. HCFs exposed to high concentrations of PM0.49 exhibited dysregulation of DNA methylation machinery, characterised by increased expression of DNMT1 and DNMT3A/B. Markers associated with fibroblast activation and pathogenic activation, including COL1A1 and α-SMA, were significantly induced following PM0.49 exposure, whereas these alterations were attenuated following 5-Aza treatment. NP-based delivery of 5-Aza attenuated PM0.49-induced HCF activation with reduced cytotoxicity under chronic exposure conditions. Bulk RNA sequencing identified transcriptomic alterations associated with PM0.49 exposure that were partially modulated by 5-Aza-NP treatment, with selected findings validated by RT-qPCR. Exposure to a smoke haze-period PM0.49 preparation from a biomass burning-affected rural site in Chiang Mai, Thailand, induced pathogenic HCF activation with molecular findings consistent with dysregulation of DNA methylation machinery. 5-Aza-NP attenuated PM0.49-induced fibroblast activation and modulated associated transcriptomic alterations, suggesting a potential epigenetic-based therapeutic strategy against PM0.49-induced cardiac fibroblast dysfunction. These findings warrant further validation across diverse PM compositions and sampling conditions.
PMID:42461493 | DOI:10.1007/s12012-026-10161-4