Mice with cardiomyocyte-specific disruption of the endothelin-1 gene are resistant to hyperthyroid cardiac hypertrophy

Ralph V. Shohet, Yaz Y. Kisanuki, Xiao Song Zhao, Zakir Siddiquee, Fatima Franco, Masashi Yanagisawa

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Abstract

Endothelin 1 (ET-1), a potent vasoconstrictor peptide expressed by endothelium, is also produced in the heart in response to a variety of stresses. It induces hypertrophy in cultured cardiac myocytes but only at concentrations far greater than those found in plasma. We tested whether ET-1 generated by cardiac myocytes in vivo is a local signal for cardiac hypertrophy. To avoid the perinatal lethality seen in systemic ET-1-null mice, we used the Cre/IoxP system to generate mice with cardiac myocyte-specific disruption of the ET-1 gene. We used the α-myosin heavy chain promoter to drive expression of Cre and were able to obtain 75% reduction in ET-1 mRNA in cardiac myocytes isolated from these mice at baseline and after stimulation, in vivo, for 24 h with tri-iodothyronine (T3). Necropsy measurements of cardiac mass indexed for body weight showed a 57% reduction in cardiac hypertrophy in response to 16 days of exogenous T3 in mice homozygous for the disrupted ET-1 allele compared to siblings with an intact ET-1 gene. Moreover, in vivo MRI showed only a 3% increase in left ventricular mass indexed for body weight in mice with the disrupted allele after 3 weeks of T3 treatment versus a 27% increase in mice with an intact ET-1 gene. A reduced hypertrophic response was confirmed by planimetry of cardiac myocytes. We conclude that ET-1, produced locally by cardiac myocytes, and acting in a paracrine/autocrine manner, is an important signal for myocardial hypertrophy that facilitates the response to thyroid hormone.

Original languageEnglish (US)
Pages (from-to)2088-2093
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number7
DOIs
StatePublished - Feb 17 2004

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Cardiomegaly
Endothelin-1
Hyperthyroidism
Cardiac Myocytes
Genes
Hypertrophy
Alleles
Body Weight
Myosin Heavy Chains
Vasoconstrictor Agents
Thyroid Hormones
Endothelium
Messenger RNA
Peptides

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Mice with cardiomyocyte-specific disruption of the endothelin-1 gene are resistant to hyperthyroid cardiac hypertrophy. / Shohet, Ralph V.; Kisanuki, Yaz Y.; Zhao, Xiao Song; Siddiquee, Zakir; Franco, Fatima; Yanagisawa, Masashi.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, No. 7, 17.02.2004, p. 2088-2093.

Research output: Contribution to journalArticle

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