Targeted inhibition of calcineurin attenuates cardiac hypertrophy in vivo.
The Ca(2+)-calmodulin-activated Ser/Thr protein phosphatase calcineurin and the downstream transcriptional effectors of calcineurin, nuclear factor of activated T cells, have been implicated in the hypertrophic response of the myocardium. Recently, the calcineurin inhibitory agents cyclosporine A and FK506 have been extensively used to evaluate the importance of this signaling pathway in rodent models of cardiac hypertrophy. However, pharmacologic approaches have rendered equivocal results necessitating more specific or genetic-based inhibitory strategies. In this regard, we have generated Tg mice expressing the calcineurin inhibitory domains of Cain/Cabin-1 and A-kinase anchoring protein 79 specifically in the heart. DeltaCain and DeltaA-kinase-anchoring protein Tg mice demonstrated reduced cardiac calcineurin activity and reduced hypertrophy in response to catecholamine infusion or pressure overload. In a second approach, adenoviral-mediated gene transfer of DeltaCain was performed in the adult rat myocardium to evaluate the effectiveness of an acute intervention and any potential species dependency. DeltaCain adenoviral gene transfer inhibited cardiac calcineurin activity and reduced hypertrophy in response to pressure overload without reducing aortic pressure. These results provide genetic evidence implicating calcineurin as an important mediator of the cardiac hypertrophic response in vivo.
De Windt
L J
LJ
Divisions of Molecular Cardiovascular Biology and Cardiology, Department of Pediatrics, Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
Lim
H W
HW
Bueno
O F
OF
Liang
Q
Q
Delling
U
U
Braz
J C
JC
Glascock
B J
BJ
Kimball
T F
TF
del Monte
F
F
Hajjar
R J
RJ
Molkentin
J D
JD
D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing; D000256:Adenoviridae; D000818:Animals; D001794:Blood Pressure; D019703:Calcineurin / Q000235:genetics / Q000502:physiology*; D065095:Calcineurin Inhibitors; D006332:Cardiomegaly / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D002316:Cardiotonic Agents / Q000009:adverse effects; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D015870:Gene Expression; D005822:Genetic Vectors; D006321:Heart / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D007545:Isoproterenol / Q000009:adverse effects; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D051381:Rats
D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing; C415703:Akap5 protein, rat; C113151:Cabin1 protein, mouse; D065095:Calcineurin Inhibitors; D002316:Cardiotonic Agents; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D019703:Calcineurin; D007545:Isoproterenol