Regulation of cardiac hypertrophy in vivo by the stress-activated protein kinases/c-Jun NH(2)-terminal kinases.
Cardiac hypertrophy often presages the development of heart failure. Numerous cytosolic signaling pathways have been implicated in the hypertrophic response in cardiomyocytes in culture, but their roles in the hypertrophic response to physiologically relevant stimuli in vivo is unclear. We previously reported that adenovirus-mediated gene transfer of SEK-1(KR), a dominant inhibitory mutant of the immediate upstream activator of the stress-activated protein kinases (SAPKs), abrogates the hypertrophic response of neonatal rat cardiomyocytes to endothelin-1 in culture. We now report that gene transfer of SEK-1(KR) to the adult rat heart blocks SAPK activation by pressure overload, demonstrating that the activity of cytosolic signaling pathways can be inhibited by gene transfer of loss-of-function mutants in vivo. Furthermore, gene transfer of SEK-1(KR) inhibited pressure overload-induced cardiac hypertrophy, as determined by echocardiography and several postmortem measures including left ventricular (LV) wall thickness, the ratio of LV weight to body weight, cardiomyocyte diameter, and inhibition of atrial natriuretic factor expression. Our data suggest that the SAPKs are critical regulators of cardiac hypertrophy in vivo, and therefore may serve as novel drug targets in the treatment of hypertrophy and heart failure.
Choukroun
G
G
Medical Services, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Hajjar
R
R
Fry
S
S
del Monte
F
F
Haq
S
S
Guerrero
J L
JL
Picard
M
M
Rosenzweig
A
A
Force
T
T
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000502:physiology; D001794:Blood Pressure; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D006332:Cardiomegaly / Q000201:enzymology* / Q000209:etiology / Q000517:prevention & control; D004789:Enzyme Activation; D015870:Gene Expression; D018014:Gene Transfer Techniques; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D009154:Mutation; D009206:Myocardium / Q000201:enzymology; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
D009320:Atrial Natriuretic Factor; D011494:Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases