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© The Rockefeller University Press, 0021-9525/1998//523 $5.00
The Journal of Cell Biology, Volume 142, Number 2, , 1998 523-535

Articles

Stimulation of the p38 Mitogen-activated Protein Kinase Pathway in Neonatal Rat Ventricular Myocytes by the G Protein–coupled Receptor Agonists, Endothelin-1 and Phenylephrine: A Role in Cardiac Myocyte Hypertrophy?



Angela Clerk*, Ashour Michael{ddagger}, and Peter H. Sugden{ddagger}

* Division of Biomedical Sciences, Imperial College School of Medicine, Charing Cross Campus, London W6 8RF, United Kingdom; and {ddagger} NHLI Division (Cardiac Medicine), Imperial College School of Medicine, Royal Brompton Campus, London SW3 6LY, United Kingdom

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.

Key Words: hypertrophy • cardioprotection • mitogen-activated protein kinases • adrenergic agonists • endothelin-1

Abbreviations used in this paper: ERK, extracellularly responsive kinase; ET-1, endothelin-1; FPLC, fast protein liquid chromatography; GPCR, G protein–coupled receptor; HSP, heat shock protein; MAPK, mitogen-activated protein kinase; MKK, MAPK kinase; MAPKAPK2, MAPK-activated protein kinase 2; MEK, MAPK/ERK kinase; MBP, myelin basic protein; β-MHC, β-myosin heavy chain; PBS, Ca2+/Mg2+-free Dulbecco's phosphate-buffered saline; PE, phenylephrine; PTX, pertussis toxin; SAPK/JNK, stress-activated protein kinase/c-Jun NH2-terminal kinase.


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