Original Article

Altered signal pathway in granulocytes from patients with hypercholesterolemia

Correspondence to: Gabriella Fóris

In the present study the signal transduction of the formyl-Met-Leu-Phe receptor was studied in granulocytes obtained from control subjects and patients with elevated low density lipoprotein levels. According to our results, 10 nM formyl-Met-Leu-Phe in control cells activates phospholipase C inducing a pronounced inositol phosphate production followed by a Ca²⁺ signal from intracellular pools. The pertussis toxin-sensitive O₂^- generation and leukotriene synthesis were moderate. In contrast, in granulocytes from hypercholesterolemic patients, formyl-Met-Leu-Phe triggered an intensive pertussis toxin-insensitive oxidative burst and leukotriene synthesis. The inositol trisphosphate and Ca²⁺ signals were decreased significantly in granulocytes of hypercholesterolemic patients and seem to be dependent on the extracellular Ca²⁺ content. Furthermore, in the resting granulocytes of hypercholesterolemic patients the [Ca²⁺]i and the membrane-bound protein kinase C activity were higher than in controls, the time of normalization after the low Ca²⁺ signal was delayed, while the membrane fluidity was decreased.

Our results suggest that in these ex vivo experiments, the high level of circulating low density lipoprotein in patients can affect the membrane composition of granulocytes leading to altered signal transduction by the formyl-Met-Leu-Phe receptor, to altered Ca²⁺ pump-activity, and protein kinase C translocation.—Paragh, G., E. Kovács, I. Seres, T. Keresztes, Z. Balogh, J. Szabó, F. Teichmann, and G. Fóris. Altered signal pathway in granulocytes from patients with hypercholesterolemia. J. Lipid Res. 1999. 40: 1728;–1733.

Supplementary key words: hypercholesterolemia, granulocytes, formyl-Met-Leu-Phe, Ca²⁺ signal, inositol phosphates, leukotrienes, O₂^- generation, membrane fluidity

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