Segregation of atrial-specific and inducible expression of an atrial natriuretic factor transgene in an in vivo murine model of cardiac hypertrophy

Howard A. Rockman, Robert S. Ross, Adrienne N. Harris, Kirk U. Knowlton, Mark E. Steinhelper, Loren Field, John Ross, Kenneth R. Chien

Research output: Contribution to journalArticle

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Abstract

To study the mechanisms that activate expression of the atrial natriuretic factor (ANF) gene during pressure-induced hypertrophy, we have developed and characterized an in vivo murine model of myocardial cell hypertrophy. We employed microsurgical techniques to produce a stable 35- to 45-mmHg pressure gradient across the thoracic aorta of the mouse that is associated with rapid and transient expression of an immediate-early gene program (c-fos/c-jun/junB/Egr-1/nur-77), an increase in heart weight/body weight ratio, and up-regulation of the endogenous ANF gene. These responses that are identical to those in cultured cell and other in vivo models of hypertrophy. To determine whether tissue-specific and inducible expression of the ANF gene can be segregated, we used a transgenic mouse line in which 500 base pairs of the human ANF promoter region directs atrial-specific expression of the simian virus 40 large tumor antigen (T antigen), with no detectable expression in the ventricles. Thoracic banding of these mice led to a 20-fold increase in the endogenous ANF mRNA in the ventricle but no detectable expression of the T-antigen marker gene. This result provides evidence that atrial-specific and inducible expression of the ANF gene can be segregated, suggesting that a distinct set of regulatory cis sequences may mediate the up-regulation of the ANF gene during in vivo pressure overload hypertrophy. This murine model demonstrates the utility of microsurgical techniques to study in vivo cardiac physiology in transgenic mice and should allow the application of genetic approaches to identify the mechanisms that activate ventricular expression of the ANF gene during in vivo hypertrophy.

Original languageEnglish
Pages (from-to)8277-8281
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume88
Issue number18
StatePublished - 1991

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Cardiomegaly
Atrial Natriuretic Factor
Transgenes
Hypertrophy
Genes
Pressure
Transgenic Mice
Up-Regulation
Immediate-Early Genes
Simian virus 40
Viral Tumor Antigens
Neoplasm Antigens
Thoracic Aorta
Genetic Promoter Regions
Base Pairing
Cultured Cells
Thorax
Body Weight
Weights and Measures
Messenger RNA

ASJC Scopus subject areas

  • General
  • Genetics

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Segregation of atrial-specific and inducible expression of an atrial natriuretic factor transgene in an in vivo murine model of cardiac hypertrophy. / Rockman, Howard A.; Ross, Robert S.; Harris, Adrienne N.; Knowlton, Kirk U.; Steinhelper, Mark E.; Field, Loren; Ross, John; Chien, Kenneth R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 88, No. 18, 1991, p. 8277-8281.

Research output: Contribution to journalArticle

Rockman, Howard A. ; Ross, Robert S. ; Harris, Adrienne N. ; Knowlton, Kirk U. ; Steinhelper, Mark E. ; Field, Loren ; Ross, John ; Chien, Kenneth R. / Segregation of atrial-specific and inducible expression of an atrial natriuretic factor transgene in an in vivo murine model of cardiac hypertrophy. In: Proceedings of the National Academy of Sciences of the United States of America. 1991 ; Vol. 88, No. 18. pp. 8277-8281.
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