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Molecular and Cellular Biology, November 2003, p. 8226-8232, Vol. 23, No. 22
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.22.8226-8232.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Cardiomyocyte-Specific Endothelin A Receptor Knockout Mice Have Normal Cardiac Function and an Unaltered Hypertrophic Response to Angiotensin II and Isoproterenol

Rafal M. Kedzierski,1,2 Paul A. Grayburn,3,4 Yaz Y. Kisanuki,1,2 Clay S. Williams,1,2 Robert E. Hammer,1 James A. Richardson,4,5 Micheal D. Schneider,6 and Masashi Yanagisawa1,2,4,7*

Howard Hughes Medical Institute,1 Departments of Molecular Genetics,2 Internal Medicine,3 and Pathology,5 The Donald W. Reynolds Cardiovascular Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390,4 Molecular Cardiology Unit, Baylor College of Medicine, Houston, Texas 77030,6 ERATO Yanagisawa Orphan Receptor Project, Japan Science and Technology Corp., Tokyo 135-0064, Japan7

Received 26 February 2003/ Returned for modification 26 March 2003/ Accepted 11 August 2003

Even though endothelin is recognized as an important vasoregulatory molecule, the roles of endothelin receptors in specific cell types are not yet fully understood. Mice with a null mutation in endothelin A receptor gene (ETA) or in the gene of its ligand (endothelin 1) die neonatally due to craniofacial and cardiac abnormalities. This early lethality has in the past hindered studies on the role of endothelin in cardiovascular physiology and pathophysiology. To overcome this obstacle, we utilized the cre/loxP technology to generate mice in which the ETA gene could be deleted specifically in cardiomyocytes. The cre recombinase transgene driven by the {alpha}-myosin heavy-chain promoter deleted the floxed ETA allele specifically in the hearts of these mice, resulting in a 78% reduction in cardiac ETA mRNA level compared to wild-type controls. Cardiomyocyte-specific ETA knockout animals are viable and exhibit normal growth, cardiac anatomy, and cardiac contractility, as assessed by echocardiography. In addition, these animals exhibit hypertrophic and contractile responses to 10-day infusion of angiotensin II or isoproterenol similar to those observed in control animals. These results indicate that in adult mice cardiac ETA receptors are not necessary for either baseline cardiac function or stress-induced response to angiotensin II or isoproterenol.

* Corresponding author. Mailing address: Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390-9050. Phone: (214) 648-5623. Fax: (214) 648-5068. E-mail: Masashi.Yanagisawa{at}UTSouthwestern.edu.

Molecular and Cellular Biology, November 2003, p. 8226-8232, Vol. 23, No. 22
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.22.8226-8232.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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