Hypertrophy is the principal response of the heart to overload from any cause, including hypertension, myocardial infarction, valvar heart disease, and dilated cardiomyopathy.

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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.

"Stress-regulated" mitogen-activated protein kinases (SR-MAPKs) comprise the stress-activated protein kinases (SAPKs)/c-Jun N-terminal kinases (JNKs) and the p38-MAPKs. In the perfused heart, ischemia/reperfusion activates SR-MAPKs. Although the agent(s) directly responsible is unclear, reactive oxygen species are generated during ischemia/reperfusion. We have assessed the ability of oxidative stress (as exemplified by H 2 O 2 ) to activate SR-MAPKs in the perfused heart and compared it with the effect of ischemia/reperfusion. H 2 O 2 activated both SAPKs/JNKs and p38-MAPK. Maximal activation by H 2 O 2 in both cases was observed at 0.5 mM. Whereas activation of p38-MAPK by H 2 O 2 was comparable to that of ischemia and ischemia/reperfusion, activation of the SAPKs/JNKs was less than that of ischemia/ reperfusion. As with ischemia/reperfusion, there was minimal activation of the ERK MAPK subfamily by H 2 O 2 . MAPK-activated protein kinase 2 (MAPKAPK2), a downstream substrate of p38-MAPKs, was activated by H 2 O 2 to a similar extent as with ischemia or ischemia/ reperfusion. In all instances, activation of MAPKAPK2 in perfused hearts was inhibited by SB203580, an inhibitor of p38-MAPKs. Perfusion of hearts at high aortic pressure (20 kilopascals) also activated the SRMAPKs and MAPKAPK2. Free radical trapping agents (dimethyl sulfoxide and N-t-butyl-␣-phenyl nitrone) inhibited the activation of SR-MAPKs and MAPKAPK2 by ischemia/reperfusion. These data are consistent with a role for reactive oxygen species in the activation of SR-MAPKs during ischemia/reperfusion.Ischemic and hypertensive myocardial disease is currently a major cause of mortality and morbidity. In these conditions, the heart is exposed to numerous cell stresses including increased production of reactive oxygen species (ROS), 1 ionic imbalances, osmotic stress, mechanical stress, and metabolic deprivation (reviewed in Refs. 1-4). In numerous cell lines, primary cultures, and tissues, cellular stresses activate "stress-regulated" mitogen-activated protein kinases (SR-MAPKs) (reviewed in Refs. 5 and 6). There are two relatively well characterized SR-MAPK families, the stress-activated protein kinases (SAPKs) and the p38-MAPKs. SAPKs are alternatively known as the c-Jun N-terminal kinases (JNKs), although, strictly speaking, the JNK terminology applies to the human enzymes, whereas the SAPK terminology applies to the rat enzymes.Substrates for SAPKs/JNKs include the transcription factors c-Jun (7, 8), ATF-2 (9 -12), and Elk-1 (13, 14). Phosphorylation of these transcription factors in their trans-activation domains leads to an increase in their ability to trans-activate transcription. p38-MAPK (15, 16) (alternatively known as cytokinesuppressive antiinflammatory drug-binding protein (17), reactivating kinase (18), Mxi2 (19), or stress-activated protein kinase-2 (20)) is a mammalian homolog of the yeast osmosensing protein kinase HOG-1. Like SAPKs/JNKs, p38-MAPKs also phosphorylate transcription factors (ATF2 (11), CHOP/ GADD153 (21), and MEF2C (22)),...

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