Retinoic Acid Alleviates Accelerated Atherosclerosis in Diesel Exhaust–Derived PM2.5–Exposed ApoE−/− Mice by Enhancing eNOS–NO Coupling

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.