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Regulation of Endothelial Production of C-Type Natriuretic Peptide by Interaction between Endothelial Cells and Macrophages¹

Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, and the Department of Internal Medicine and Clinical Research Center (H.I.), National Utano Hospital, Kyoto, Japan

Address all correspondence and requests for reprints to: Hiroshi Itoh, M.D., Ph.D., Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin kawaharacho, Sakyo-ku, Kyoto 606, Japan. E-mail: hiito{at}kuhp.kyoto-u.ac.jp

We demonstrated endothelial production of C-type natriuretic peptide (CNP), the third member of the natriuretic peptide family, and its regulation by cytokines, including tumor necrosis factor- (TNF). We thus proposed that CNP can control vascular tone and growth as an endothelium-derived relaxing peptide. We also revealed the marked elevation of plasma CNP concentration in patients with septic shock, in which TNF plays a significant part. As the interaction between endothelial cells (EC) and monocytes-macrophages plays a pivotal role in the pathogenesis of atherosclerosis, we investigated the effect of coculture of EC and macrophages on endothelial production of CNP. We used a human monocytic leukemia cell line, THP-1, which differentiates into macrophages when treated with phorbol 12-myristate 13-acetate. The coculture of EC and THP-1-derived macrophages enhanced CNP secretion by more than 10-fold compared with the single culture of EC or the coculture of EC and THP-1 without phorbol 12-myristate 13-acetate treatment. Prevention of direct contact between EC and THP-1-derived macrophages did not attenuate the increase in CNP secretion. Northern blotting revealed the augmentation of CNP messenger RNA expression in EC in the coculture. We detected TNF in the conditioned medium from the coculture of EC and THP-1-derived macrophages. Furthermore, anti-TNF antibody inhibited the stimulation of CNP secretion in the coculture. CNP at a concentration of 1 nM did not stimulate cGMP production in EC or THP-1-derived macrophages, but it elevated cGMP production significantly in vascular smooth muscle cells. These results indicate that endothelial production of CNP is stimulated mainly by TNF released from THP-1-derived macrophages in the coculture. Endothelial CNP at the enhanced level may be one of the vascular mediators to regulate local vascular tone and growth through cGMP production by vascular smooth muscle cells, suggesting the potential significance of endothelial CNP in atherosclerosis.

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