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.
Sadoshima
Junichi
J
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
Montagne
Olivier
O
Wang
Qian
Q
Yang
Guiping
G
Warden
Jill
J
Liu
Jing
J
Takagi
Gen
G
Karoor
Vijaya
V
Hong
Chull
C
Johnson
Gary L
GL
Vatner
Dorothy E
DE
Vatner
Stephen F
SF
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