A requirement for the rac1 GTPase in the signal transduction pathway leading to cardiac myocyte hypertrophy.
We have used adenoviral-mediated gene transfer of a constitutively active (V12rac1) and dominant negative (N17rac1) isoform of rac1 to assess the role of this small GTPase in cardiac myocyte hypertrophy. Expression of V12rac1 in neonatal cardiac myocytes results in sarcomeric reorganization and an increase in cell size that is indistinguishable from ligand-stimulated hypertrophy. In addition, V12rac1 expression leads to an increase in atrial natriuretic peptide secretion. In contrast, expression of N17rac1, but not a truncated form of Raf-1, attenuated the morphological hypertrophy associated with phenylephrine stimulation. Consistent with the observed effects on morphology, expression of V12rac1 resulted in an increase in new protein synthesis, while N17rac1 expression inhibited phenylephrine-induced leucine incorporation. These results suggest rac1 is an essential element of the signaling pathway leading to cardiac myocyte hypertrophy.
Pracyk
J B
JB
Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Tanaka
K
K
Hegland
D D
DD
Kim
K S
KS
Sethi
R
R
Rovira
I I
II
Blazina
D R
DR
Lee
L
L
Bruder
J T
JT
Kovesdi
I
I
Goldshmidt-Clermont
P J
PJ
Irani
K
K
Finkel
T
T
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000032:analysis; D006332:Cardiomegaly / Q000503:physiopathology*; D048429:Cell Size / Q000502:physiology; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D020558:GTP Phosphohydrolases / Q000502:physiology; D019204:GTP-Binding Proteins / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D018014:Gene Transfer Techniques; D009206:Myocardium / Q000166:cytology*; D010656:Phenylephrine / Q000494:pharmacology; D014176:Protein Biosynthesis; D019908:Proto-Oncogene Proteins c-raf / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012518:Sarcomeres / Q000648:ultrastructure; D015398:Signal Transduction / Q000502:physiology*; D020744:rac GTP-Binding Proteins
D010656:Phenylephrine; D009320:Atrial Natriuretic Factor; D019908:Proto-Oncogene Proteins c-raf; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; D020744:rac GTP-Binding Proteins