Angiotensin II Induces Tumor Necrosis Factor Biosynthesis in the Adult Mammalian Heart Through a Protein Kinase C–Dependent Pathway
- 7 May 2002
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation
- Vol. 105 (18), 2198-2205
- https://doi.org/10.1161/01.cir.0000015603.84788.47
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 (10−7mol/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.Keywords
This publication has 16 references indexed in Scilit:
- Angiotensin II and gene expression in the kidneyMaterials, 1998
- Sphingosine Mediates the Immediate Negative Inotropic Effects of Tumor Necrosis Factor-α in the Adult Mammalian Cardiac MyocyteJournal of Biological Chemistry, 1997
- Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: A report from the studies of left ventricular dysfunction (SOLVD)Journal of the American College of Cardiology, 1996
- Cardiac Myotrophin Exhibits rel/NF-κB Interacting Activity in VitroPublished by Elsevier BV ,1996
- Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation.Genes & Development, 1995
- Tumor necrosis factor-alpha gene and protein expression in adult feline myocardium after endotoxin administration.JCI Insight, 1995
- Phosphorylation of IκBα Precedes but Is Not Sufficient for Its Dissociation from NF-κBMolecular and Cellular Biology, 1995
- Activation of human peripheral monocytes by angiotensin IIFEBS Letters, 1994
- Progression of left ventricular dysfunction secondary to coronary artery disease, sustained neurohormonal activation and effects of ibopamine therapy during long-term therapy with angiotensin-converting enzyme inhibitorThe American Journal of Cardiology, 1994
- Elevated Circulating Levels of Tumor Necrosis Factor in Severe Chronic Heart FailureNew England Journal of Medicine, 1990