Endothelin-1 synthesis and endothelin B receptor expression in human coronary artery smooth muscle cells and monocyte-derived macrophages is up-regulated by low density lipoproteins

Endothelin-1 (ET-1) is a potent vasoconstrictive peptide exerting its effec ts predominantly by paracrine and autocrine mechanisms. ET-1 acts as a mito gen and co-mitogen on vascular smooth muscle cells, and accumulating eviden ce suggests that ETA is involved in the pathogenesis of atherosclerosis. De position of low density lipoproteins (LDL) in the vessel wall is known to p lay a crucial role in the development of atherosclerotic lesions. In the pr esent study, we have investigated the effect of native LDL (nLDL) and oxida tively modified LDL (oxLDL) on ET-1 synthesis and endothelin receptor expre ssion in cultured human coronary artery smooth muscle cells and human monoc yte-derived macrophages. Native LDL and oxLDL induced a significant stimula tion of ET-1 release and ET-1 mRNA expression in human coronary artery smoo th muscle cells and monocyte-derived macrophages. Antibodies against the sc avenger receptor CD 36 significantly reduced the oxLDL-induced stimulation of ET-1 synthesis. The antioxidants trolox and probucol did not significant ly inhibit the LDL-induced rise of ET-1 release. Endothelin B receptor expr ession was up-regulated in both cell types after incubation with nLDL and o xLDL. In coronary smooth muscle cells, endothelin A receptor expression was slightly increased by LDL, whereas endothelin A receptor was not detectabl e in monocyte-derived macrophages. Coronary artery smooth muscle cells secr eted a more than 150-fold higher amount of immunoreactive ET-1 into the cel l culture medium than monocyte-derived macrophages. In summary, the present data. demonstrating a LDL-induced upregulation of the endothelin system in coronary smooth muscle cells and in monocyte-derived macrophages, provide further support for a pathophysiological role of endothelin in coronary ath erosclerosis and suggest that ET-1 might be involved in mediating the ather ogenic effects of LDL. (C) 2001 Academic Press.