M. Woods et al., Endothelin-1 is induced by cytokines in human vascular smooth muscle cells: Evidence for intracellular endothelin-converting enzyme, MOLEC PHARM, 55(5), 1999, pp. 902-909
Endothelin-1 (ET-1) is the predominant endothelin isopeptide generated by t
he vascular wall and therefore appears to be the most important peptide inv
olved in regulation of cardiovascular events. Many pathologic conditions ar
e associated with elevations of ET-1 in the blood vessel wall. Because thes
e conditions are often cytokine driven, we examined the effects of a mixtur
e of cytokines on ET-1 production in human vascular smooth muscle cells (VS
MCs) derived from internal mammary artery and saphenous vein (SV), Incubati
on of IMA and SV VSMCs with tumor necrosis factor-alpha (10 ng/ml) and inte
rferon-gamma (1000 U/ml) in combination for up to 48 h markedly elevated th
e expression of mRNA for prepro-ET-1 and the release of ET-1 into the cultu
re medium. This cytokine-stimulated release of ET-1 was inhibited by a seri
es of dual endothelin-converting enzyme (ECE)/neutral endopeptidase inhibit
ors, phosphoramidon, CGS 26303, and CGS 26393, with an accompanying increas
e in big ET-1 release but with no effect on expression of mRNA for prepro-E
T-1. These same compounds were 10 times more potent at inhibiting the conve
rsion of exogenously applied big ET-1 to ET-1, ECE-1b/c mRNA is present in
SV VSMCs, however no ECE-1 a is present in these cells. Thus VSMCs most pro
bably contain, like endothelial cells, an intracellular ECE responsible for
the endogenous synthesis of ET-1. Under the influence of pro-inflammatory
mediators the vascular smooth muscle can therefore become an important site
of ET-1 production, as has already been established for the dilator mediat
ors nitric oxide, prostaglandin I-2, and prostaglandin E-2.