A role for the p38 mitogen-activated protein kinase pathway in myocardial cell growth, sarcomeric organization, and cardiac-specific gene expression

Dietmar Zechner, Donna J. Thuerauf, Deanna S. Hanford, Patrick M. McDonough, Christopher C. Glembotski

Research output: Contribution to journalArticlepeer-review

277 Scopus citations

Abstract

Three hallmark features of the cardiac hypertrophic growth program are increases in cell size, sarcomeric organization, and the induction of certain cardiac-specific genes. All three features of hypertrophy are induced in cultured myocardial cells by α1-adrenergic receptor agonists, such as phenylephrine (PE) and other growth factors that activate mitogen-activated protein kinases (MAPKs). In this study the MAPK family members extracellular signal-regulated kinase (ERK), c-jun NH2-terminal kinase (JNK), and p38 were activated by transfecting cultured cardiac myocytes with constructs encoding the appropriate kinases possessing gain-of-function mutations. Transfected cells were then analyzed for changes in cell size, sarcomeric organization, and induction of the genes for the A- and B-type natriuretic peptides (NPs), as well as the α-skeletal actin (α-SkA) gene. While activation of JNK and/or ERK with MEKK1(COOH) or Raf-1 BXB, respectively, augmented cell size and effected relatively modest increases in NP and α-SkA promoter activities, neither upstream kinase conferred sarcomeric organization. However, transfection with MKK6 (Glu), which specifically activated p38, augmented cell size, induced NP and α-SkA promoter activities by up to 130- fold, and elicited sarcomeric organization in a manner similar to PE. Moreover, all three growth features induced by MKK6 (Glu) or PE were blocked with the p38-specific inhibitor, SB 203580. These results demonstrate novel and potentially central roles for MKK6 and p38 in the regulation of myocardial cell hypertrophy.

Original languageEnglish (US)
Pages (from-to)115-127
Number of pages13
JournalJournal of Cell Biology
Volume139
Issue number1
DOIs
StatePublished - Oct 6 1997
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology

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