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

Abstract

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 (ET_A ) 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 ET_A gene could be deleted specifically in cardiomyocytes. The cre recombinase transgene driven by the α-myosin heavy-chain promoter deleted the floxed ET_A allele specifically in the hearts of these mice, resulting in a 78% reduction in cardiac ET_A mRNA level compared to wild-type controls. Cardiomyocyte-specific ET_A 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 ET_A receptors are not necessary for either baseline cardiac function or stress-induced response to angiotensin II or isoproterenol.

ACKNOWLEDGMENTS

We thank Kristine E. Kamm for helpful discussions and Mark Valasek for editorial suggestions. We also thank Sahar Seyedkalal and Shelley Dixon for technical help.

M.Y. is an Investigator of the Howard Hughes Medical Institute. R.M.K. is a trainee in Medical Scientist Training Program at the University of Texas Southwestern Medical Center at Dallas. This study is supported in part by research funds from the W. M. Keck Foundation, the Perot Family Foundation, and the ERATO project of Japan Science and Technology Corp.