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Vol. 55, Issue 5, 902-909, May 1999
Vascular Inflammation, Endothelin-1 (ET-1) is the predominant endothelin isopeptide generated
by the vascular wall and therefore appears to be the most important
peptide involved in regulation of cardiovascular events. Many
pathologic conditions are associated with elevations of ET-1 in the
blood vessel wall. Because these conditions are often cytokine driven,
we examined the effects of a mixture of cytokines on ET-1 production in
human vascular smooth muscle cells (VSMCs) derived from internal
mammary artery and saphenous vein (SV). Incubation of IMA and SV VSMCs
with tumor necrosis factor-
(10 ng/ml) and interferon-
(1000 U/ml) in combination for up to 48 h markedly elevated the
expression of mRNA for prepro-ET-1 and the release of ET-1 into
the culture medium. This cytokine-stimulated release of ET-1 was
inhibited by a series of dual endothelin-converting enzyme
(ECE)/neutral endopeptidase inhibitors, phosphoramidon, CGS 26303, and
CGS 26393, with an accompanying increase in big ET-1 release but with
no effect on expression of mRNA for prepro-ET-1. These same compounds
were 10 times more potent at inhibiting the conversion of exogenously
applied big ET-1 to ET-1. ECE-1b/c mRNA is present in SV VSMCs, however
no ECE-1a is present in these cells. Thus VSMCs most probably
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 mediators nitric oxide, prostaglandin
I2, and prostaglandin E2.
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics
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