E prostanoid receptor‐3 promotes oxidized low‐density lipoprotein‐induced human aortic smooth muscle cells inflammation

AIM: The progression of atherosclerosis can lead to the occurrence of multiple cardiovascular diseases (coronary heart disease, etc.). E prostanoid receptor‐3 (EP3) is known to participate in the progression of atherosclerosis. This study aimed to investigate the mechanism by which EP3 modulates the development of atherosclerosis. METHODS AND RESULTS: ApoE(−/−) mice were used to construct in vivo model of atherosclerosis. Human aortic smooth muscle cells (HASMCs) were stimulated with oxidized low‐density lipoprotein (ox‐LDL) to construct in vitro model of atherosclerosis. mRNA expressions were assessed by qRT‐PCR, and western blot was applied to assess the protein levels. CCK‐8 assay was applied to assess the cell viability. The inflammatory cytokines levels were assessed by enzyme‐linked immunosorbent assay, and flow cytometry was applied to assess cell apoptosis. In vivo experiment was constructed to investigate the impact of EP3 in atherosclerosis development. L‐798106 (EP3 inhibitor) significantly inhibited the levels of pro‐inflammatory cytokines in atherosclerosis in vivo. EP3 inhibitor (L‐798106) significantly reversed ox‐LDL‐caused HASMCs injury via inhibiting the apoptosis and inflammatory responses (P < 0.05). The levels of interleukin‐17 (IL‐17) and intercellular adhesion molecule‐1 (ICAM‐1) in HASMCs were elevated by ox‐LDL, whereas L‐798106 or knockdown of cyclic AMP (cAMP) response element‐binding protein (CREB) notably restored this phenomenon (P < 0.05). EP3 overexpression further aggravated ox‐LDL‐induced inflammation in HASMCs, and EP3 up‐regulated the levels of IL‐17 and ICAM‐1 in ox‐LDL‐treated HASMCs (P < 0.05). EP3 up‐regulation promoted the inflammatory responses in ox‐LDL‐treated HASMCs through mediation of cAMP/protein kinase A (PKA)/CREB/IL‐17/ICAM‐1 axis (P < 0.05). CONCLUSIONS: EP3 inhibitor alleviates ox‐LDL‐induced HASMC inflammation via mediation of cAMP/PKA/CREB/IL‐17/ICAM‐1 axis. Our study might shed new lights on discovering novel strategies against atherosclerosis.