Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NFAT signaling.

Abstract

The MAPKs are important transducers of growth and stress stimuli in virtually all eukaryotic cell types. In the mammalian heart, MAPK signaling pathways have been hypothesized to regulate myocyte growth in response to developmental signals or physiologic and pathologic stimuli. Here we generated cardiac-specific transgenic mice expressing dominant-negative mutants of p38alpha, MKK3, or MKK6. Remarkably, attenuation of cardiac p38 activity produced a progressive growth response and myopathy in the heart that correlated with the degree of enzymatic inhibition. Moreover, dominant-negative p38alpha, MKK3, and MKK6 transgenic mice each showed enhanced cardiac hypertrophy following aortic banding, Ang II infusion, isoproterenol infusion, or phenylephrine infusion for 14 days. A mechanism underlying this enhanced-growth profile was suggested by the observation that dominant-negative p38alpha directly augmented nuclear factor of activated T cells (NFAT) transcriptional activity and its nuclear translocation. In vivo, NFAT-dependent luciferase reporter transgenic mice showed enhanced activation in the presence of the dominant-negative p38alpha transgene before and after the onset of cardiac hypertrophy. More significantly, genetic disruption of the calcineurin Abeta gene rescued hypertrophic cardiomyopathy and depressed functional capacity observed in p38-inhibited mice. Collectively, these observations indicate that reduced p38 signaling in the heart promotes myocyte growth through a mechanism involving enhanced calcineurin-NFAT signaling.

• Authors: Julian C Braz, Orlando F Bueno, Qiangrong Liang, Benjamin J Wilkins, Yan-Shan Dai, Stephanie Parsons, Joseph Braunwart, Betty J Glascock, Raisa Klevitsky, Thomas F Kimball, Timothy E Hewett, Jeffery D Molkentin
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 111 Issue 10 Pg. 1475-86 (May 2003) ISSN: 0021-9738 [Print] United States
• PMID: 12750397 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• DNA-Binding Proteins
• NFATC Transcription Factors
• Nuclear Proteins
• Transcription Factors
• Protein-Tyrosine Kinases
• Calcium-Calmodulin-Dependent Protein Kinases
• Mitogen-Activated Protein Kinase 14
• Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 3
• MAP Kinase Kinase 6
• Map2k3 protein, mouse
• Map2k6 protein, mouse
• Mitogen-Activated Protein Kinase Kinases
• Calcineurin

Topics

• Animals
• Calcineurin (deficiency, genetics, metabolism)
• Calcium-Calmodulin-Dependent Protein Kinases (genetics, metabolism)
• Cardiomyopathy, Hypertrophic (genetics, pathology, physiopathology)
• Cells, Cultured
• DNA-Binding Proteins (metabolism)
• Disease Progression
• Gene Targeting
• Genes, Dominant
• Genes, Reporter
• In Vitro Techniques
• MAP Kinase Kinase 3
• MAP Kinase Kinase 6
• Mice
• Mice, Transgenic
• Mitogen-Activated Protein Kinase 14
• Mitogen-Activated Protein Kinase Kinases (genetics, metabolism)
• Mitogen-Activated Protein Kinases (antagonists & inhibitors, genetics, metabolism)
• Myocytes, Cardiac (cytology, metabolism)
• NFATC Transcription Factors
• Nuclear Proteins
• Protein-Tyrosine Kinases (genetics, metabolism)
• Rats
• Signal Transduction (physiology)
• Transcription Factors (metabolism)
• Transgenes
• Up-Regulation