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Vol. 59, Issue 2, 163-169, February 2001
Department of Experimental Therapeutics, William Harvey Research
Institute, St. Bartholomew's and the Royal London School of Medicine
and Dentistry, Queen Mary and Westfield College, Charterhouse Square
Campus, London, EC1M 6BQ, UK
Endothelin-1 (ET-1) is secreted from endothelial and vascular smooth
muscle cells (VSMC) after intracellular hydrolysis of big ET-1 by
endothelin converting enzyme (ECE). The metallopeptidase called ECE-1
is widely thought to be the physiological ECE, but unequivocal evidence
of this role has yet to be provided. Endothelial cells express four
isoforms of ECE-1 (ECE-1a, ECE-1b, ECE-1c, and ECE-1d), but the
identity of ECE-1 isoforms expressed in VSMC is less clear. Here, we
describe the characterization of ECE-1 isoforms in bovine pulmonary
artery smooth muscle cells (BPASMC) and the effect on ET-1 synthesis of
an antisense oligodeoxynucleotide (ODN) to ECE-1c. Reverse
transcriptase-polymerase chain reaction (RT-PCR) evaluation of total
RNA from BPASMC showed that ECE-1a and ECE-1d were not expressed.
Sequencing of cloned ECE-1 cDNA products and semiquantitative RT-PCR
demonstrated that ECE-1b and ECE-1c were expressed in BPASMC, with
ECE-1c being the predominant isoform. Basal release of ET-1 from BPASMC
was low. Treatment for 24 h with tumor necrosis factor-
(TNF) stimulated ET-1 production by up to 10-fold with parallel
increases in levels of preproET-1 mRNA. Levels of ECE-1c mRNA were also
raised after TNF, whereas amounts of ECE-1b mRNA were decreased
significantly. Treatment of BPASMC with a phosphorothioate antisense
ODN to ECE-1c caused a marked reduction in ECE-1c mRNA levels and ECE-1
protein levels. However, basal and TNF-stimulated ET-1 release were
largely unaffected by the ECE-1c antisense ODN despite the inhibition
of ECE-1c synthesis. Hence, an endopeptidase distinct from ECE-1 is
mainly responsible big ET-1 processing in BPASMC.
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