Why the study?
Does the absence of MEKK1 prevent cardiac hypertrophy and dysfunction induced by Galphaq in mice and cultured myocytes?
Does the absence of MEKK1 prevent cardiac hypertrophy and dysfunction induced by Galphaq in mice and cultured myocytes?
MEKK1 gene deletion prevents Galphaq-induced cardiac hypertrophy and dysfunction in vivo, identifying it as a potential therapeutic target for heart failure.
MEKK1 deletion prevents Gαq-induced hypertrophy and dysfunction in mice; leaves open therapeutic targeting in human HF.
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.
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Minamino et al. (2002) studied this question.
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