The MEKK1-JNK pathway plays a protective role in pressure overload but does not mediate cardiac hypertrophy.
Mitogen-activated protein kinase kinase kinase (MEKK1) mediates activation of c-Jun NH(2)-terminal kinase (JNK). Although previous studies using cultured cardiac myocytes have suggested that the MEKK1-JNK pathway plays a key role in hypertrophy and apoptosis, its effects in cardiac hypertrophy and apoptosis are not fully understood in adult animals in vivo. We examined the role of the MEKK1-JNK pathway in pressure-overloaded hearts by using mice deficient in MEKK1. We found that transverse aortic banding significantly increased JNK activity in Mekk1(+/+) but not Mekk1(-/-) mice, indicating that MEKK1 mediates JNK activation by pressure overload. Nevertheless, pressure overload caused significant levels of cardiac hypertrophy and expression of atrial natriuretic factor in Mekk1(-/-) animals, which showed higher mortality and lung/body weight ratio than were seen in controls. Fourteen days after banding, Mekk1(-/-) hearts were dilated, and their left ventricular ejection fraction was low. Pressure overload caused elevated levels of apoptosis and inflammatory lesions in these mice and produced a smaller increase in TGF-beta and TNF-alpha expression than occurred in wild-type controls. Thus, MEKK1 appears to be required for pressure overload-induced JNK activation and cytokine upregulation but to be dispensable for pressure overload-induced cardiac hypertrophy. MEKK1 also prevents apoptosis and inflammation, thereby protecting against heart failure and sudden death following cardiac pressure overload.
Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark 07103, USA. Sadoshju@umdnj.edu
Junichi
J
Sadoshima
Olivier
O
Montagne
Qian
Q
Wang
Guiping
G
Yang
Jill
J
Warden
Jing
J
Liu
Gen
G
Takagi
Vijaya
V
Karoor
Chull
C
Hong
Gary L
GL
Johnson
Dorothy E
DE
Vatner
Stephen F
SF
Vatner
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D009320:Atrial Natriuretic Factor / Q000235:genetics; D001794:Blood Pressure / Q000502:physiology*; D004789:Enzyme Activation; D015870:Gene Expression; D017379:Hypertrophy, Left Ventricular / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D048031:JNK Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D009320:Atrial Natriuretic Factor; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482578:Map3k1 protein, mouse