Abstract | BACKGROUND: METHODS AND RESULTS: We observed marked reduction in immunoreactive signal for plakoglobin at cardiac myocyte junctions in patients with sarcoidosis and giant cell myocarditis, both highly arrhythmogenic forms of myocarditis associated with granulomatous inflammation. In contrast, plakoglobin signal was not depressed in lymphocytic (nongranulomatous) myocarditis. To determine whether cytokines might promote dislocation of plakoglobin from desmosomes, we incubated cultures of neonatal rat ventricular myocytes with selected inflammatory mediators. Brief exposure to low concentrations of interleukin (IL)-17, tumor necrosis factor-α (TNF-α), and IL-6 ( cytokines implicated in granulomatous myocarditis) caused translocation of plakoglobin from cell-cell junctions to intracellular sites, whereas other potent cytokines implicated in nongranulomatous myocarditis had no effect, even at much higher concentrations. We also observed myocardial expression of IL-17 and TNF-α and elevated levels of serum inflammatory mediators, including IL-6R, IL-8, monocyte chemoattractant protein 1, and macrophage inflammatory protein 1β, in patients with ARVC (all P<0.0001 compared with controls). CONCLUSIONS: The results suggest novel disease mechanisms involving desmosomal proteins in granulomatous myocarditis and implicate cytokines, perhaps derived in part from the myocardium, in disruption of desmosomal proteins and arrhythmogenesis in ARVC.
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Authors | Angeliki Asimaki, Harikrishna Tandri, Elizabeth R Duffy, Jeffrey R Winterfield, Shannon Mackey-Bojack, Maria M Picken, Leslie T Cooper, David J Wilber, Frank I Marcus, Cristina Basso, Gaetano Thiene, Adalena Tsatsopoulou, Nikos Protonotarios, William G Stevenson, William J McKenna, Shiva Gautam, Daniel G Remick, Hugh Calkins, Jeffrey E Saffitz |
Journal | Circulation. Arrhythmia and electrophysiology
(Circ Arrhythm Electrophysiol)
Vol. 4
Issue 5
Pg. 743-52
(Oct 2011)
ISSN: 1941-3084 [Electronic] United States |
PMID | 21859801
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- CCL2 protein, human
- Chemokine CCL2
- Chemokine CCL4
- Interleukin-17
- Interleukin-6
- Interleukin-8
- Tumor Necrosis Factor-alpha
- gamma Catenin
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Topics |
- Adolescent
- Adult
- Aged
- Animals
- Arrhythmias, Cardiac
(blood, etiology, physiopathology)
- Autopsy
- Biopsy
- Cardiomyopathies
(blood, etiology, physiopathology)
- Case-Control Studies
- Cells, Cultured
- Chemokine CCL2
(blood)
- Chemokine CCL4
(blood)
- Child
- Desmosomes
(metabolism)
- Female
- Humans
- Intercellular Junctions
(drug effects, metabolism)
- Interleukin-17
(metabolism, pharmacology)
- Interleukin-6
(metabolism, pharmacology)
- Interleukin-8
(blood)
- Male
- Middle Aged
- Models, Animal
- Myocarditis
(metabolism, pathology, physiopathology)
- Myocytes, Cardiac
(drug effects, metabolism)
- Rats
- Rats, Wistar
- Sarcoidosis
(metabolism, physiopathology)
- Signal Transduction
(physiology)
- Tumor Necrosis Factor-alpha
(metabolism, pharmacology)
- Ventricular Dysfunction, Right
(blood, etiology, physiopathology)
- Young Adult
- gamma Catenin
(metabolism)
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