Myocardial expression of endothelin-2 is altered reciprocally to that of endothelin-1 during ischemia of cardiomyocytes in vitro and during heart failure in vivo
Y. Kakinuma et al., Myocardial expression of endothelin-2 is altered reciprocally to that of endothelin-1 during ischemia of cardiomyocytes in vitro and during heart failure in vivo, LIFE SCI, 65(16), 1999, pp. 1671-1683
We and other groups have reported that endothelin (ET) -1 expression in the
heart is altered in the setting of heart diseases. We have also reported t
hat myocardial ET-I is involved in the progression of heart failure, and th
at an ET receptor antagonist improves long-term survival in heart failure (
Nature 384: 353-355, 1996). However, the role of myocardial ET-2 in disease
states are not known. To characterize the role of ET-2, we used a) the fai
ling hearts of rats with heart failure caused by myocardial infarction, and
b) primary cultured cardiomyocytes subjected to hypoxia. In the failing he
art in vivo, ET-1 mRNA increased by 390% compared with that in the non-fail
ing heart, while ET-2 mRNA drastically decreased by 88%. Thus, gene express
ion of ET1 and ET-2 was reciprocally altered in the failing heart in vivo.
In in vitro studies, reciprocal alterations in ET-1 and ET-2 gene expressio
n were also observed in isolated primary cultured cardiomyocytes, subjected
to hypoxia. Specifically, acute hypoxic stress induced a significant incre
ase (360% of the basal level) in ET-2 mRNA expression compared with that in
normoxic cells, whereas it decreased ET-1 mRNA expression by 62% in primar
y cultured cardiomyocytes. Although these two crucial conditions, i.e., hea
rt failure in vivo and acute hypoxic stress in vitro, are pathophysiologica
lly distinct from each other, reciprocal alteration of ET-1 and ET-2 gene e
xpression was observed in both cases. To further investigate the regulatory
mechanism of the altered gene expression, luciferase analysis was performe
d using primary cultured cardiomyocytes. ET-2 promoter, which is the 5'-fla
nking region of preproET-2 gene (5'ET-2), showed a marked increase in lucif
erase activity during acute hypoxia. In contrast, the luciferase activity o
f 5'ET-1 (ET-1 promoter) did not change in response to hypoxic stress. The
present study suggests that there are transcriptionally distinct regulatory
mechanisms for ET-1 and ET-2 expression in cardiomyocytes, and therefore t
his study may provide a new aspect of cardiac ET system that not only ET-I
but also ET-2 can be participated in the pathophysiological conditions.