Activation of macrophages: influence of extracellular calcium and of the calmodulin antagonist Fendilin

Abstract

The presence and function of macrophages in the arterial wall are regarded as very important for the induction and progression of arteriosclerotic lesions. One main characteristic of these cells is their ability to release free radicals and other reactive products influencing their vicinity. In order to get more information on the complex metabolic reactions leading to increased radical formation, we were interested in the influence of extracellular calcium as well as of the calmodulin antagonist Fendilin on luminol-enhanced chemoluminescence induced by zymosan stimulation in macrophages obtained by alveolar lavage of rabbits. The results show that in some preparations no dependency, in other a strong increasing effect of extracellular calcium was found on total radical liberation as well as on activation by zymosan. Hypercholesterolemia alters macrophage reactivity so that extracellular calcium gains a strong influence on the activation process. Fendilin in vitro has only a small inhibitory effect on macrophage activation, indicating that the calcium-calmodulin pathway is of minor importance in the activation process. However, the long term effect of hypercholesterolemia on macrophages, inducing a decreased activation and alterations in the time course of radical release, are inhibited when Fendilin is applied to the animals during the same period. Therefore, one can conclude that hypercholesterolemia exerts its effect on macrophages at least in part by alterations in cellular calcium homeostasis.

Zusammenfassung

Makrophagen stellen eine wichtige zelluläre Komponente der arteriosklerotischen Plaque dar. Ihre Bedeutung für die Atherogenese und die von ihnen ausgehenden Wechselwirkungen sind noch nicht vollständig geklärt [3]. Dem bei Aktivierung — z.B. durch Phagozytose — zu beobachtenden ‚respiratory burst‘, eine stark vermehrte Freisetzung von reaktiven Sauerstoffmetaboliten, wie H₂O₂, O₂ etc. [1], kommt sowohl im Hinblick auf die oxidative Modifizierung von LDL (Low density lipoprotein) als auch auf die zytotoxische Wirkung von Makrophagen eine wichtige Rolle zu [4]. Bei dieser Aktivierung wird eine Vielzahl von Stoffwechselwegen der Makrophagen beeinflußt, wobei Ca²⁺-Ionen eine wichtige Signalfunktion haben.