Endothelin-1 production is enhanced by rotenone, a mitochondrial complex I inhibitor, in cultured rat cardiomyocytes

Koh Ichi Yuhki, Takashi Miyauchi, Yoshihiko Kakinuma, Nobuyuki Murakoshi, Seiji Maeda, Katsutoshi Goto, Iwao Yamaguchi, Takahiko Suzuki

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

In chronic heart failure and acute myocardial infarction, the tissue level of endothelin (ET) -1 in the heart, as well as its plasma level, has been reported to increase markedly. There is, however, little information about what in these pathologic conditions leads to increased production of ET-1, and which type of cell in the heart produces ET-1. We examined the mRNA and peptide expression of ET-1 using cultured rat neonatal cardiomyocytes, in which mitochondrial dysfunction was induced by rotenone, a mitochondrial respiratory chain complex I inhibitor, because one of the common features in failing or ischemic hearts is an alteration in energy metabolism due to mitochondrial dysfunction. Rotenone increased glucose use by the culture cells within 12 h of addition without affecting cell viability, and depressed the mitochondrial membrane potential after 72 h, indicating the induction of mitochondrial dysfunction in cardiomyocytes. Rotenone induced significant increase in the expression level of mRNA for ET-1 within 1 h of addition. In accordance with this finding, immunoreactive ET-1 in culture medium increased 3 times after 24 h of incubation, suggesting active secretion of ET-1 from cultured cells treated with rotenone. Immunocytochemical analysis verified significant increase of ET-1 peptide in cardiomyocytes, confirming the production of ET-1 by cardiomyocytes. These results suggest that derangement of mitochondrial function in cardiomyocytes itself could lead to the increased production of ET-1 in cardiomyocytes, and that this mechanism may contribute to the increased production of ET-1 in failing and ischemic hearts.

Original languageEnglish
Pages (from-to)850-858
Number of pages9
JournalJournal of Cardiovascular Pharmacology
Volume38
Issue number6
DOIs
Publication statusPublished - 2001
Externally publishedYes

Keywords

  • Endothelin
  • Heart failure
  • Mitochondria
  • Myocardial infarction
  • Rotenone

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

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