The biological function of the intronic microRNA-28 (miR-28) may be associated with the biological roles of its host gene, LIM domain lipoma‑preferred partner (LPP). LPP has been reported to promote smooth muscle cell migration in arterial injury and atherosclerosis. However, the mechanism of miR‑28 in atherosclerosis remains unclear. In the current study, the aim was to validate the inhibitory effect of miR‑28‑5p on extracellular signal‑regulated kinase 2 (ERK2), to investigate its biological role in atherosclerosis and its association with cardiovascular disease. Western blotting and stem‑loop reverse transcription‑quantitative polymerase chain reaction combined with TaqMAN microRNA analysis was conducted. The current study demonstrated that miR‑28‑5p upregulated the expression of ATP‑binding cassette transporter A1 (ABCA1) via the inhibition of ERK2 in HepG2 cells. In addition, increased levels of plasma miR‑28‑5p were positively correlated with the levels of high‑density lipoprotein cholesterol in patients with unstable angina. This suggests that miR-28-5p participates in atherosclerosis via ERK2-mediated upregulation of the ABCA1 pathway.