Activation of nuclear factor-kappaB is necessary for myotrophin-induced cardiac hypertrophy.

Abstract

The transcription factor nuclear factor-kappaB (NF-kappaB) regulates expression of a variety of genes involved in immune responses, inflammation, proliferation, and programmed cell death (apoptosis). Here, we show that in rat neonatal ventricular cardiomyocytes, activation of NF-kappaB is involved in the hypertrophic response induced by myotrophin, a hypertrophic activator identified from spontaneously hypertensive rat heart and cardiomyopathic human hearts. Myotrophin treatment stimulated NF-kappaB nuclear translocation and transcriptional activity, accompanied by IkappaB-alpha phosphorylation and degradation. Consistently, myotrophin-induced NF-kappaB activation was enhanced by wild-type IkappaB kinase (IKK) beta and abolished by the dominant-negative IKKbeta or a general PKC inhibitor, calphostin C. Importantly, myotrophin-induced expression of two hypertrophic genes (atrial natriuretic factor [ANF] and c-myc) and also enhanced protein synthesis were partially inhibited by a potent NF-kappaB inhibitor, pyrrolidine dithio-carbamate (PDTC), and calphostin C. Expression of the dominant-negative form of IkappaB-alpha or IKKbeta also partially inhibited the transcriptional activity of ANF induced by myotrophin. These findings suggest that the PKC-IKK-NF-kappaB pathway may play a critical role in mediating the myotrophin-induced hypertrophic response in cardiomyocytes.

• Authors: Sudhiranjan Gupta, Nicole H Purcell, Anning Lin, Subha Sen
• Journal: The Journal of cell biology (J Cell Biol) Vol. 159 Issue 6 Pg. 1019-28 (Dec 23 2002) ISSN: 0021-9525 [Print] United States
• PMID: 12486112 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Alkaloids
• Benzophenanthridines
• DNA, Complementary
• Growth Substances
• I-kappa B Proteins
• Intercellular Signaling Peptides and Proteins
• NF-kappa B
• NFKBIA protein, human
• Naphthalenes
• Nfkbia protein, rat
• Phenanthridines
• RNA, Messenger
• myotrophin
• NF-KappaB Inhibitor alpha
• chelerythrine
• Luciferases
• Protein Kinase C
• calphostin C

Topics

• Alkaloids
• Animals
• Animals, Newborn
• Benzophenanthridines
• Blotting, Northern
• Blotting, Western
• Cell Nucleus (metabolism)
• Cells, Cultured
• Cytoplasm (metabolism)
• DNA, Complementary (metabolism)
• Dose-Response Relationship, Drug
• Enzyme Activation
• Genes, Dominant
• Growth Substances (metabolism)
• Hypertrophy
• I-kappa B Proteins (metabolism)
• Immunohistochemistry
• Intercellular Signaling Peptides and Proteins (metabolism)
• Luciferases (metabolism)
• Microscopy, Confocal
• Microscopy, Fluorescence
• Myocardium (cytology, pathology)
• NF-KappaB Inhibitor alpha
• NF-kappa B (metabolism)
• Naphthalenes (metabolism)
• Phenanthridines (metabolism)
• Phosphorylation
• Protein Binding
• Protein Kinase C (metabolism)
• Protein Transport
• RNA, Messenger (metabolism)
• Rats
• Rats, Sprague-Dawley
• Rats, Wistar
• Time Factors
• Transcription, Genetic
• Transfection