The role of 27-hydroxycholesterol in hypercholesterolemia-associated exacerbation of apical periodontitis and therapeutic potential of felodipine

Abstract

Background/purposeStudies have demonstrated a relation between hypercholesterolemia and development of apical periodontitis (AP), but the underlying mechanism is uncertain. 27-hydroxycholesterol (27HC), produced by cytochrome P450 27A1 (CYP27A1)-catalyzed hydroxylation of cholesterol, is known to possess pro-inflammatory activity. Felodipine is an anti-hypertensive agent able to inhibit CYP27A1. The study aimed to examine the inflammatory response of macrophages to 27HC and the relation between 27HC accumulation and progression of experimental AP. The therapeutic effect of felodipine was also evaluated. Materials and methodsJ774 murine macrophages were used. Expressions of cyclooxygenase-2 (COX-2) and C–C motif chemokine ligand 20 (CCL20) were examined by Western blot. Concentrations of 27HC were assessed by enzyme-linked immunosorbent assay. Fluorescence assay was used to evaluate cholesterol levels. AP was induced in male rats receiving high fat/high cholesterol diet (HFHCD) or normal diet (ND). Micro-computed tomography and immunohistochemistry were employed to evaluate disease progression and therapeutic effect of felodipine. ResultsCholesterol enhanced production of 27HC which in turn stimulated COX-2 and CCL20 synthesis by macrophages. HFHCD consumption significantly augmented serum and lesion tissue levels of 27HC in rats. Lesion size and infiltration of COX-2+ and interleukin (IL)-17+ cells increased in parallel with 27HC accumulation in AP. Felodipine suppressed cholesterol-induced 27HC production in macrophages. Felodipine treatment reduced serum and tissue levels of 27HC in HFHCD rats and concurrently mitigated AP propagation. ConclusionOur results suggest a pivotal role of 27HC in hypercholesterolemia-exacerbated AP. By repressing 27HC production, felodipine may have the potential to help mitigate AP in obese individuals.