Protein Kinase C, but Not Tyrosine Kinases or Ras, Plays a Critical Role in Angiotensin II-induced Activation of Raf-1 Kinase and Extracellular Signal-regulated Protein Kinases in Cardiac Myocytes

Cardiac hypertrophy, an important adaptational response, is associated with up-regulation of the immediate early gene, c-jun, which encodes the c-Jun transcription factor. c-Jun may feed back to up-regulate its own transcription and, since the c-Jun N-terminal kinase (JNK) family of mitogen-activated protein kinases (MAPKs) phosphorylate c-Jun(Ser-63/73) to increase its transactivating activity, JNKs are thought to be the principal factors involved in c-jun up-regulation. Hypertrophy in primary cultures of cardiac myocytes is induced by endothelin-1, phenylephrine or PMA, probably through activation of one or more of the MAPK family. These three agonists increased c-jun mRNA with the rank order of potency of PMAendothelin-1> phenylephrine. Up-regulation of c-jun mRNA by endothelin-1 was attenuated by inhibitors of protein kinase C (GF109203X) and the extracellular signal-regulated kinase (ERK) cascade (PD98059 or U0126), but not by inhibitors of the JNK (SP600125) or p38-MAPK (SB203580) cascades. Hyperosmotic shock (0.5M sorbitol) powerfully activates JNKs, but did not increase c-jun mRNA. These data suggest that ERKs, rather than JNKs, are required for c-jun up-regulation. However, endothelin-1 and phenylephrine induced greater up-regulation of c-Jun protein than PMA and phosphorylation of c-Jun(Ser-63/73) correlated with the level of c-Jun protein. Up-regulation of c-Jun protein by endothelin-1 was attenuated by inhibitors of protein kinase C and the ERK cascade, probably correlating with a primary input of ERKs into transcription. In addition, SP600125 inhibited the phosphorylation of c-Jun(Ser-63/73), attenuated the increase in c-Jun protein induced by endothelin-1 and increased the rate of c-Jun degradation. Thus whereas ERKs are the principal MAPKs required for c-jun transcription, JNKs are necessary to stabilize c-Jun for efficient up-regulation of the protein.

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Angiotensin II Induces Translocation of Protein Kinase C α and ε in Neonatal Rat Cardiac Myocytes

Microscopy and Microanalysis ◽

10.1017/s1431927600031159 ◽

2001 ◽

Vol 7 (S2) ◽

pp. 1016-1017

Author(s):

Tara A. Bullard ◽

Edie Goldsmith ◽

Robert L. Price

Keyword(s):

Signal Transduction ◽

Protein Kinase C ◽

Angiotensin Ii ◽

Protein Kinase ◽

Cardiac Myocytes ◽

Heart Development ◽

Neonatal Rat ◽

Ang Ii ◽

Kinase C ◽

Transduction Mechanisms

Angiotensin II (Ang II) plays an important role in heart development and has been shown to stimulate the formation of premyofibrils and differentiation of cardiac myocytes. Ang II signaling occurs through two types of receptors, the AT1 and AT2 receptors, both of which appear to play a role in the development of the myocardium. Through the use of specific Ang II receptor blockers it as been shown that blocking the AT1 receptor with Losartan (Merck) inhibits the formation of premyofibrils and sarcomere formation and that blocking the AT2 receptor with PD123,319 (Parke-Davis) inhibits the formation of trabeculae in the developing heart.In a number of cases it has been shown that signal transduction mechanisms operate through different growth factor receptors and elicit specific responses within a cell type. Protein kinase C (PKC) is a family of closely related signal transduction enzymes that phosphorylate proteins on serine or threonine residues.

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