Retinoic Acid Alleviates Accelerated Atherosclerosis in Diesel Exhaust–Derived PM2.5–Exposed ApoE−/− Mice by Enhancing eNOS–NO Coupling
- 1Department of Oriental Pharmacy, College of Pharmacy, Wonkwang University, Iksan 54538, Republic of Korea
- 2Wonkwang-Oriental Medicines Research Institute, Wonkwang University, Iksan 54538, Republic of Korea
- 3Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, 460, Iksan-daero, Iksan 54538, Republic of Korea
Abstract
Background: Respiratory exposure to fine particulate matter (PM2.5), including diesel exhaust particles (DEPs), is a major air pollutant associated with pulmonary inflammation and cardiovascular diseases. This study investigated the protective effects and underlying mechanisms of retinoic acid (RA) against PM2.5-induced lung injury and accelerated atherosclerosis. Methods: Differentially expressed genes (DEGs) were identified from lung tissues of five non-smokers and six patients with chronic obstructive pulmonary disease obtained from the Gene Expression Omnibus (GEO) database and analyzed using the L1000CDS2, which identified RA as a candidate therapeutic compound. The Comparative Toxicogenomics Database was subsequently used to investigate curated associations between lung and cardiovascular disorders, suggesting the endothelial nitric oxide synthase (eNOS)/nitric oxide (NO) signaling pathway as a candidate mechanism for experimental validation. ApoE−/− mice were exposed to DEP via a nebulization chamber and treated orally with all-trans retinoic acid (1 or 5 mg/kg/day) for 8 weeks. Results: RA significantly reduced C-X-C motif chemokine ligand 1/2 (CXCL1/2) levels in bronchoalveolar lavage fluid and decreased pulmonary expression of Muc5ac, IL-1β, IL-6, and TNF-α. RA also lowered blood pressure, improved serum lipid profiles, and attenuated inflammatory cell infiltration and arterial wall thickening in the thoracic aorta. In HUVECs, RA significantly increased guanosine triphosphate (GTP) cyclohydrolase-1 (GTPCH-1) expression, eNOS phosphorylation, tetrahydrobiopterin (BH4) levels, and the BH4/BH2 ratio. Conclusion: These findings suggest that the activation of the GTPCH-1/BH4/eNOS coupling pathway contributes to the protective effects of RA against DEP-induced cardiovascular injury.
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BibTeX
@article{han2026retinoic,
title = {{Retinoic Acid Alleviates Accelerated Atherosclerosis in Diesel Exhaust–Derived PM2.5–Exposed ApoE−/− Mice by Enhancing eNOS–NO Coupling}},
author = {Ji-Ye Han and Byung Hyuk Han and Se Hoon Jang and Bori Lee and Young-Mi Lee and Yun Jung Lee},
journal = {Nutrients},
year = {2026},
month = nov,
doi = {10.3390/nu18213680},
url = {https://www.mdpi.com/2072-6643/18/21/3680},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Retinoic Acid Alleviates Accelerated Atherosclerosis in Diesel Exhaust–Derived PM2.5–Exposed ApoE−/− Mice by Enhancing eNOS–NO Coupling
AU - Ji-Ye Han
AU - Byung Hyuk Han
AU - Se Hoon Jang
AU - Bori Lee
AU - Young-Mi Lee
AU - Yun Jung Lee
PY - 2026
DA - 2026/11/06
JO - Nutrients
DO - 10.3390/nu18213680
UR - https://www.mdpi.com/2072-6643/18/21/3680
AB - Background: Respiratory exposure to fine particulate matter (PM2.5), including diesel exhaust particles (DEPs), is a major air pollutant associated with pulmonary inflammation and cardiovascular diseases. This study investigated the protective effects and underlying mechanisms of retinoic acid (RA) against PM2.5-induced lung injury and accelerated atherosclerosis. Methods: Differentially expressed genes (DEGs) were identified from lung tissues of five non-smokers and six patients with chronic obstructive pulmonary disease obtained from the Gene Expression Omnibus (GEO) database and analyzed using the L1000CDS2, which identified RA as a candidate therapeutic compound. The Comparative Toxicogenomics Database was subsequently used to investigate curated associations between lung and cardiovascular disorders, suggesting the endothelial nitric oxide synthase (eNOS)/nitric oxide (NO) signaling pathway as a candidate mechanism for experimental validation. ApoE−/− mice were exposed to DEP via a nebulization chamber and treated orally with all-trans retinoic acid (1 or 5 mg/kg/day) for 8 weeks. Results: RA significantly reduced C-X-C motif chemokine ligand 1/2 (CXCL1/2) levels in bronchoalveolar lavage fluid and decreased pulmonary expression of Muc5ac, IL-1β, IL-6, and TNF-α. RA also lowered blood pressure, improved serum lipid profiles, and attenuated inflammatory cell infiltration and arterial wall thickening in the thoracic aorta. In HUVECs, RA significantly increased guanosine triphosphate (GTP) cyclohydrolase-1 (GTPCH-1) expression, eNOS phosphorylation, tetrahydrobiopterin (BH4) levels, and the BH4/BH2 ratio. Conclusion: These findings suggest that the activation of the GTPCH-1/BH4/eNOS coupling pathway contributes to the protective effects of RA against DEP-induced cardiovascular injury.
SN - 2072-6643
ER -