Neuropeptides induced a pronounced and statin-sensitive dysregulation of mevalonate cycle in human monocytes of patients with hypercholesterolemia

Angiotensin 11 (Ang 11) and leptin generate statin-inhibitable superoxide anion production that accounts for only part of the entire superoxide anion production. In our recent studies, we aimed at elucidating whether Ang 11 and leptin, affecting the intensity of the mevalonate cycle, are able to increase endogenous cholesterol synthesis. Furthermore, we compared the superoxide anion and cholesterol production capability of monocytes of healthy control volunteers and monocytes obtained from patients with hypercholesterolemia (HC). We also studied the differences of the produced statin-inhibitable superoxide anion and cholesterol synthesis in control and HC-monocytes, depending on the applied stimulating ligands. In control and HC-monocytes - stimulated by Ang 11, leptin, fenyl-Me-Leu-Phe (FMLP), phorbol-12-myristate-13-acetate (PMA) and A23187 - we determined the proportion of mevalonate cycle-dependent and -independent superoxide and cholesterol production, using lovastatin (Lov), and 25-hydroxycholesterol (25-HC). According to our results; (1) superoxide anion generation in HC-monocytes was elevated after Ang 11, leptin and FMLP-stimulation, whereas PMA and A23187-stimulation had lower stimulating effect in HC than in control cells. (2) Cholesterol synthesis was increased only after stimulation with Ang 11 and leptin. (3) The Ang 11 and leptin-induced total superoxide anion generation and cholesterol synthesis were more elevated in HC than in control monocytes. (4) In contrast, the increase in Lov and 25-HC sensitive cholesterol synthesis were higher in resting, but lower in stimulated HC monocytes than in control cells. Summarizing our results, we concluded that Ang 11 and leptin are involved in enhancement of endogenous cholesterol synthesis through a statin-sensitive pathway. (c) 2006 Published by Elsevier Ltd.