Induction of monocytic adhesion by a 12/15-lipoxygenase-mediated lipid hydroperoxide accumulation in hyperglycemia

Purpose: Diabetes mellitus leads to a monocytic dysfunction by induction of oxidative stress. The dysfunction accelerates an accumulation of monocytic cells, which drives atherosclerosis. The underlying molecular mechanisms of the diabetes-oxidative stress pathways are incompletely understood. Therefore, we investigated the impact of 12/15 lipoxygenase (LOX) in monocyte dysfunction in diabetes mellitus (DM).

Methods: Primary human monocytes from non-DM or DM patients were isolated from peripheral blood using negative selection methods. Moreover, monocytes from healthy controls were preconditioned in either normoglycemia (NG) or hyperglycemia (HG). The lipid peroxidation end product malondialdehyde (MDA) was detected by HPLC. Moreover, LOX was pharmacological inhibited by treatment with AA861. Enhanced lipid peroxide environment was mimicked using the lipid peroxidation by product 15-HPETE. Adhesion molecule expression was measured by RT-QPCR and FACS.

Results: DM-monocytes and monocytes preconditioned in HG display elevated LOX genes and increased MDA. Additional treatment with AA861 significantly reduced HG-induced MDA increase. HG significantly induced the expression of adhesion molecules. We detected an upregulation of CD18 (70%, p-value=0.01), CD11b (2-fold, p-value=0.0008) and CD61 (60%, p-value=0.02) on the monocytic cell surface and also demonstrated an increase in adhesion molecule genes. Additional LOX inhibition by AA861 in the presence of HG quenched the elevated adhesion molecules. Moreover, an elevation of adhesion molecules could be obtained by mimicking enhanced lipid peroxide conditions with 15-HPETE.

Conclusions: Our study reveals a direct role for DM- and HG-mediated LOX gene amplification on the monocytic adhesion molecule expression via enhanced lipid peroxide formation. Rescue of lipid peroxide generation in HG may have beneficial effects on impaired monocytic function in diabetes. However, further studies are required to understand the relationship between LOX and monocytic adhesiveness.

Interessenkonflikt

No conflicts of interest.

Publication History

Article published online:
18 April 2024