MEKK1 is essential for cardiac hypertrophy and dysfunction induced by Gq.
Signaling via mitogen-activated protein kinases is implicated in heart failure induced by agonists for G protein-coupled receptors that act via the G protein Galphaq. However, this assertion relies heavily on pharmacological inhibitors and dominant-interfering proteins and not on gene deletion. Here, we show that endogenous cardiac MAPK/ERK kinase kinase-1 (MEKK1)/(MAP3K1), a mitogen-activated protein kinase kinase kinase, is activated by heart-restricted overexpression of Galphaq in mice. In cardiac myocytes derived from embryonic stem cells in culture, homozygous disruption of MEKK1 selectively impaired c-Jun N-terminal kinase activity in the absence or presence of phenlyephrine, a Galphaq-dependent agonist. Other terminal mitogen-activated protein kinases were unaffected. In mice, the absence of MEKK1 abolished the increase in cardiac mass, myocyte size, hypertrophy-associated atrial natriuretic factor induction, and c-Jun N-terminal kinase activation by Galphaq, and improved ventricular mechanical function. Thus, MEKK1 mediates cardiac hypertrophy induced by Galphaq in vivo and is a logical target for drug development in heart disease involving this pathway.
Minamino
Tetsuo
T
Center for Cardiovascular Development and The DeBakey Heart Center, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Yujiri
Toshiaki
T
Terada
Naohiro
N
Taffet
George E
GE
Michael
Lloyd H
LH
Johnson
Gary L
GL
Schneider
Michael D
MD
D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004789:Enzyme Activation; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D015870:Gene Expression; D020962:Heterotrimeric GTP-Binding Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000201:enzymology / Q000378:metabolism
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; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins