Angiotensin II induces tumor necrosis factor biosynthesis in the adult mammalian heart through a protein kinase C-dependent pathway

Dinesh Kalra, Natarajan Sivasubramanian, Douglas L. Mann

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112 Scopus citations

Abstract

Background - Previous studies suggest that angiotensin II (Ang II) upregulates the expression of tumor necrosis factor (TNF) in nonmyocyte cell types; however, the effect of Ang II on TNF expression in the adult mammalian heart is not known. Methods and Results - To determine whether Ang II was sufficient to provoke TNF biosynthesis in the adult heart, we examined the effects of Ang II in isolated buffer-perfused Langendorff feline hearts. Ang II (10-7 mol/L) treatment resulted in a time- and dose-dependent increase in myocardial TNF mRNA and protein biosynthesis in the heart as well as in cultured adult cardiac myocytes. The effects of Ang II on myocardial TNF mRNA and protein synthesis were mediated through the angiotensin type 1 receptor (AT1R), insofar as an AT1R antagonist (AT1a) blocked the effects of Ang II, whereas an angiotensin type 2 receptor (AT2R) antagonist (AT2a) had no effect. Stimulation with Ang II led to the activation of nuclear factor-κB and activator protein-1 (AP-1), two transcription factors that are important for TNF gene expression. Nuclear factor-κB activation was accompanied by phosphorylation of IκBα on serine 32 as well as degradation of IκBα, suggesting that the effects of Ang II were mediated through an IκBα-dependent pathway. The important role of protein kinase C (PKC) was suggested by studies in which a phorbol ester triggered TNF biosynthesis, and a PKC inhibitor abrogated Ang II-induced TNF biosynthesis. Conclusions - These studies suggest that Ang II provokes TNF biosynthesis in the adult mammalian heart through a PKC-dependent pathway.

Original languageEnglish
Pages (from-to)2198-2205
Number of pages8
JournalCirculation
Volume105
Issue number18
DOIs
StatePublished - May 7 2002

Keywords

  • Angiotensin
  • Genes
  • Growth substances
  • Heart failure
  • Proteins

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