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J. Cell Biol.,
Volume 142, Number 2, July 27, 1998 523-535
* Division of Biomedical Sciences, Imperial College School of Medicine, Charing Cross Campus, London W6 8RF, United
Kingdom; and We examined the activation of the p38 mitogen-activated protein kinase (p38-MAPK) pathway by
the G protein-coupled receptor agonists, endothelin-1
and phenylephrine in primary cultures of cardiac myocytes from neonatal rat hearts. Both agonists increased the phosphorylation (activation) of p38-MAPK by
~12-fold. A p38-MAPK substrate, MAPK-activated
protein kinase 2 (MAPKAPK2), was activated approximately fourfold and 10 µM SB203580, a p38-MAPK inhibitor, abolished this activation. Phosphorylation of
the MAPKAPK2 substrate, heat shock protein 25/27,
was also increased. Using selective inhibitors, activation of the p38-MAPK pathway by endothelin-1 was
shown to involve protein kinase C but not Gi/Go nor
the extracellularly responsive kinase (ERK) pathway.
SB203580 failed to inhibit the morphological changes
associated with cardiac myocyte hypertrophy induced
by endothelin-1 or phenylephrine between 4 and 24 h.
However, it decreased the myofibrillar organization
and cell profile at 48 h. In contrast, inhibition of the
ERK cascade with PD98059 prevented the increase in
myofibrillar organization but not cell profile. These
data are not consistent with a role for the p38-MAPK pathway in the immediate induction of the morphological changes of hypertrophy but suggest that it may be
necessary over a longer period to maintain the response.
NHLI Division (Cardiac Medicine), Imperial College School of Medicine, Royal Brompton Campus, London
SW3 6LY, United Kingdom
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