Cadmium Exposure Promotes Atherosclerosis by Disrupting Cholesterol Homeostasis via miR-30d-5p Regulation

Cadmium (Cd) exposure is an emerging environmental risk factor for atherosclerotic cardiovascular diseases (ASCVDs), particularly ischemic stroke (IS). MicroRNAs are potential mediators linking environmental exposure to health hazards. However, the role of miRNAs in the development of IS triggered by Cd exposure remains largely unknown. In this study, we first demonstrate that Cd exposure, even at a relatively low dosage (4 mg/L), significantly facilitates the progression of atherosclerosis in apolipoprotein E-deficient mice fed a high-fat diet. This pro-atherogenic effect was accompanied by comprehensive disturbances in systemic and vascular cholesterol homeostasis, evidenced by altered plasma lipid profiles, hepatic lipid accumulation, and dysregulated expression of key genes governing cholesterol uptake (<i>CD36</i>), efflux (<i>ABCA1</i>), and hydrolysis (<i>NCEH1</i>) within the aortic wall. Integrated transcriptomic and metabolomic analyses further corroborated the profound disruption of the lipid metabolism pathways. Through miRNA microarray, bioinformatics analysis, and qRT-PCR validation, we identified miR-30d-5p and miR-504-3p as novel epigenetic regulators mediating Cd-induced foam cell formation. Specifically, Cd treatment upregulated miR-30d-5p and downregulated miR-504-3p, which directly targeted <i>NCEH1</i> and <i>CD36</i>, respectively, thereby promoting intracellular lipid accumulation. In a case-control population (494 IS patients and 494 controls), plasma miR-30d-5p levels were positively associated with Cd exposure and partially mediated the Cd-stroke association, accounting for 16.4% of the total effect. Moreover, miR-30d-5p significantly improved the discrimination and reclassification of IS patients beyond the traditional risk factors. In summary, our findings reveal that Cd induces atherosclerosis by disrupting cholesterol homeostasis and modulating miRNA-regulated pathways with plasma miR-30d-5p serving as a potential biomarker and mediator for Cd-related ischemic stroke. Further perspective investigations are warranted to validate our findings.