The underlying mechanism for the development of
cardiac hypertrophy that advances to
heart failure is not known. Many factors have been implied to play a role in this process. Among others, we have isolated and identified
myotrophin,
a factor that stimulates myocytes growth, from spontaneously hypertensive rat (SHR) heart and patients with
dilated cardiomyopathy. The gene encoding
myotrophin has been cloned and expressed in E. coli. Recently,
myotrophin gene has been mapped and shown to be a novel gene localized in human chromosome 7q-33. To define the characteristics of each transcript and its pathophysiological significance, we examined transcripts of
myotrophin in SHR heart during progression of
hypertrophy. Northern blot analysis of
myotrophin mRNA showed multiple transcripts. We isolated and characterized various
myotrophin cDNA clones corresponding to the multiple transcripts by 5' "stretch plus" rat heart cDNA library screening. Sequence analysis of these
cDNA clones indicates that each clone has a unique
5' UTR and multiple
3' UTR with varying lengths, repeated ATTTA motifs and many polyadenylation signals. In vitro transcripts generated from all these
myotrophin-specific
cDNA clones translate in vitro to a 12-kD
protein. Among pathophysiological significance, we determined
mRNA expression in 9 days old, 3 weeks old and 31 weeks old and observed a linear increased during the progression of
hypertrophy. In WKY, this
mRNA level remained the same throughout the growth and development of
hypertrophy. Our data strongly suggest that
myotrophin appears to be a candidate gene for
cardiac hypertrophy and
heart failure.