1.4 Manidipine Inhibits the Release of Interleukin-6 (II-6) Induced by Modified Lipoprotein and by TNF-Alpha in Culture Human Endothelial Cells

Introduction. The vascular inflammation is a critical event in the formation of atherosclerotic lesions. The exposure of endothelial cells to oxidized lipoproteins or other stress like hypertension, induce the expression of pro-atherogenic cytokines including interleukin-6 (IL-6). Drugs act by targeting one of the many factors involved in these processes can have direct antiatherosclerotic effect enhancing the beneficial effect of a reduction of cardiovascular risk factors such as high cholesterol level and hypertension.

Aim. In this study we assessed t he ability of a lipophilic calcium antagonist Manidipine to reduce the release of IL-6 induced by modified lipoprotein or tumour necrosis factor-α (TNF-alpha) in human endothelial cells.

Methods. The endothelial cells isolated from human umbilical vein (HUVEC) were incubate d with acetylated LDL (AcLDL) 50 μg/ml or oxidized LDL (OxLDL) 100 μg/ml or with TNF-alpha 2 ng/ml, and treated with Manidipine 1-20 μM for 48 hours. The release of IL-6 in the media was determined by ELISA analysis.

Results. Our results showed that both AcLDL and OxLDL stimulate the secretion of IL-6 by 100% and 134% respectively. Treatment of cells with Manidipine 1 μM reduces the secretion of IL-6 from 211.6 ± 11.5 pg/ml to 122.4 ± 11.8 pg/ml (p <0.001) and from 1300.29 ± 39.5 pg/ml to 649.39 ± 22.4 pg/ml (P < 0.01), in the presence of ACLDL or OxLDL respectively. Incubation of endothelial cells with TNF-alpha increased IL-6 secretion by 56% and treatment with Manidipine 20 μM abolished this effect by 74% (TNF-alpha 437.8 ± 51.6 pg/ml and Manidipine 115.1 ± 4.7 pg/ml, p <0.05). Manidipine did no show toxicity at all the concentrations tested.

Conclusions. Manidipine is able to inhibit the release of IL-6 induced by modified lipoprotein and by TNF-alpha in culture human endothelial cells, suggesting a potential antiatherosclerotic effect of this drug.