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

Yoshihiko Kakinuma, Takashi Miyauchi*, Tsutomu Kobayashi, Koichi Yuki, Seiji Maeda, Satoshi Sakai, Katsutoshi Goto, Iwao Yamaguchi

*この研究の対応する著者

研究成果: Article査読

20 被引用数 (Scopus)

抄録

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 that myocardial ET-1 is involved in the progression of heart failure, and that 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 failing hearts of rats with heart failure caused by myocardial infarction, and b) primary cultured cardiomyocytes subjected to hypoxia. In the failing heart in vivo, ET-1 mRNA increased by 390% compared with that in the non-failing heart, while ET-2 mRNA drastically decreased by 88%. Thus, gene expression of ET-1 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 expression were also observed in isolated primary cultured cardiomyocytes, subjected to hypoxia. Specifically, acute hypoxic stress induced a significant increase (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 primary cultured cardiomyocytes. Although these two crucial conditions, i.e., heart failure in vivo and acute hypoxic stress in vitro, are pathophysiologically distinct from each other, reciprocal alteration of ET-1 and ET-2 gene expression was observed in both cases. To further investigate the regulatory mechanism of the altered gene expression, luciferase analysis was performed using primary cultured cardiomyocytes. ET-2 promoter, which is the 5'-flanking region of preproET-2 gene (5'ET-2), showed a marked increase in luciferase activity during acute hypoxia. In contrast, the luciferase activity of 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 this study may provide a new aspect of cardiac ET system that not only ET-1 but also ET-2 can be participated in the pathophysiological conditions.

本文言語English
ページ(範囲)1671-1683
ページ数13
ジャーナルLife Sciences
65
16
DOI
出版ステータスPublished - 1999 9月 10
外部発表はい

ASJC Scopus subject areas

  • 生化学、遺伝学、分子生物学(全般)
  • 薬理学、毒性学および薬学(全般)

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