(Circulation. 1996;93:1069-1072.)
© 1996 American Heart Association, Inc.
Articles |
Myocardial Endothelin
Does It Play a Role in Myocardial Failure?
From the Cardiomyopathy Program and Cardiovascular Divisions, Boston VA Medical Center and Boston University Medical Center, Boston University School of Medicine, Boston, Mass.
Correspondence to Wilson S. Colucci, MD, Cardiomyopathy Program, Boston University Medical Center, 88 E Newton St, Boston, MA 02118.
Key Words: hypertrophy • myocardium • heart failure • endothelin
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Introduction |
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Endothelin (ET) is a 21–amino acid peptide that was initially identified in 1988 by Yanagisawa and colleagues1 as a potent vasoconstrictor substance elaborated by vascular endothelial cells. Several additional features have since become apparent. First, ET is a multifunctional peptide. In addition to causing contraction of arterial and venous smooth muscle, ET exerts pleiotropic effects on numerous aspects of cardiovascular, neuroendocrine, renal, gastrointestinal, and pulmonary function. Second, although endothelial cells are its major source, ET can be synthesized by numerous other cell types including cardiac myocytes, vascular smooth muscle cells, renal tubular epithelial cells, glomerular mesangial cells, glial cells, macrophages, mast cells, and pituitary cells. Third, ET has diverse effects on gene expression, indicating that in addition to its immediate effects on cellular function, ET may exert long-term effects on cellular growth and phenotype.
ET is synthesized as an
approximately 200–amino acid
prepro-hormone. Posttranslational cleavage yields a 38– to
39–amino acid pro-ET that undergoes an additional cleavage between
Trp21-Val22 to yield mature ET. The later
cleavage is mediated by one or more "ET converting enzymes," one
of which appears to be a metal-dependent neutral
endopeptidase. Three isoforms of ET, termed ET-1, ET-2,
and ET-3, have been identified, cloned, and sequenced. Two receptors
for ET, termed ETA and ETB, also have
been identified and shown to be expressed on several
cardiovascular cell types including
endothelial cells, vascular smooth muscle cells,
cardiac myocytes, and fibroblasts.2 The receptor subtypes
bind ET isoforms with different affinities: The ETA subtype
selectively binds ET-1=ET-2>ET-3,
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