Cardiomyocyte-specific endothelin A receptor knockout mice have normal cardiac function and an unaltered hypertrophic response to angiotensin II and isoproterenol.
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 alpha-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.
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Rafal M
RM
Kedzierski
Paul A
PA
Grayburn
Yaz Y
YY
Kisanuki
Clay S
CS
Williams
Robert E
RE
Hammer
James A
JA
Richardson
Micheal D
MD
Schneider
Masashi
M
Yanagisawa
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D006332:Cardiomegaly / Q000209:etiology; D004247:DNA / Q000235:genetics; D005260:Female; D006321:Heart / Q000502:physiology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D044023:Receptor, Endothelin B / Q000235:genetics / Q000502:physiology
D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D000804:Angiotensin II; D004247:DNA; D007545:Isoproterenol