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Molecular mechanisms behind progressing chronic inflammatory dilated cardiomyopathy

BACKGROUND: Inflammatory dilated cardiomyopathy (iDCM) is a common debilitating disease with poor prognosis that often leads to heart failure and may require heart transplantation. The aim of this study was to evaluate sera and biopsy samples from chronic iDCM patients, and to investigate molecular...

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Autores principales: Bironaite, Daiva, Daunoravicius, Dainius, Bogomolovas, Julius, Cibiras, Sigitas, Vitkus, Dalius, Zurauskas, Edvardas, Zasytyte, Ieva, Rucinskas, Kestutis, Labeit, Siegfried, Venalis, Algirdas, Grabauskiene, Virginija
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4466865/
https://www.ncbi.nlm.nih.gov/pubmed/25888309
http://dx.doi.org/10.1186/s12872-015-0017-1
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author Bironaite, Daiva
Daunoravicius, Dainius
Bogomolovas, Julius
Cibiras, Sigitas
Vitkus, Dalius
Zurauskas, Edvardas
Zasytyte, Ieva
Rucinskas, Kestutis
Labeit, Siegfried
Venalis, Algirdas
Grabauskiene, Virginija
author_facet Bironaite, Daiva
Daunoravicius, Dainius
Bogomolovas, Julius
Cibiras, Sigitas
Vitkus, Dalius
Zurauskas, Edvardas
Zasytyte, Ieva
Rucinskas, Kestutis
Labeit, Siegfried
Venalis, Algirdas
Grabauskiene, Virginija
author_sort Bironaite, Daiva
collection PubMed
description BACKGROUND: Inflammatory dilated cardiomyopathy (iDCM) is a common debilitating disease with poor prognosis that often leads to heart failure and may require heart transplantation. The aim of this study was to evaluate sera and biopsy samples from chronic iDCM patients, and to investigate molecular mechanism associated with left ventricular remodeling and disease progression in order to improve therapeutic intervention. METHODS: Patients were divided into inflammatory and non-inflammatory DCM groups according to the immunohistochemical expression of inflammatory infiltrates markers: T-lymphocytes (CD3), active-memory T lymphocyte (CD45Ro) and macrophages (CD68). The inflammation, apoptosis, necrosis and fibrosis were investigated by ELISA, chemiluminescent, immunohistochemical and histological assays. RESULTS: The pro-inflammatory cytokine IL-6 was significantly elevated in iDCM sera (3.3 vs. 10.98 μg/ml; P < 0.05). Sera levels of caspase-9, −8 and −3 had increased 6.24-, 3.1- and 3.62-fold, (P < 0.05) and only slightly (1.3-, 1.22- and 1.03-fold) in biopsies. Significant release of Hsp60 in sera (0.0419 vs. 0.36 ng/mg protein; P < 0.05) suggested a mechanistic involvement of mitochondria in cardiomyocyte apoptosis. The significant MMP9/TIMP1 upregulation in biopsies (0.1931 - 0.476, P < 0.05) and correlation with apoptosis markers show its involvement in initiation of cell death and ECM degradation. A slight activation of the extrinsic apoptotic pathway and the release of hsTnT might support the progression of chronic iDCM. CONCLUSIONS: Data of this study show that significant increase of IL-6, MMP9/TIMP1 and caspases-9, −8, −3 in sera corresponds to molecular mechanisms dominating in chronic iDCM myocardium. The initial apoptotic pathway was more activated by the intramyocardial inflammation and might be associated with extrinsic apoptotic pathway through the pro-apoptotic Bax. The activated intrinsic form of myocardial apoptosis, absence of necrosis and decreased fibrosis are most typical characteristics of chronic iDCM. Clinical use of anti-inflammatory drugs together with specific anti-apoptotic treatment might improve the efficiency of therapies against chronic iDCM before heart failure occurs.
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spelling pubmed-44668652015-06-16 Molecular mechanisms behind progressing chronic inflammatory dilated cardiomyopathy Bironaite, Daiva Daunoravicius, Dainius Bogomolovas, Julius Cibiras, Sigitas Vitkus, Dalius Zurauskas, Edvardas Zasytyte, Ieva Rucinskas, Kestutis Labeit, Siegfried Venalis, Algirdas Grabauskiene, Virginija BMC Cardiovasc Disord Research Article BACKGROUND: Inflammatory dilated cardiomyopathy (iDCM) is a common debilitating disease with poor prognosis that often leads to heart failure and may require heart transplantation. The aim of this study was to evaluate sera and biopsy samples from chronic iDCM patients, and to investigate molecular mechanism associated with left ventricular remodeling and disease progression in order to improve therapeutic intervention. METHODS: Patients were divided into inflammatory and non-inflammatory DCM groups according to the immunohistochemical expression of inflammatory infiltrates markers: T-lymphocytes (CD3), active-memory T lymphocyte (CD45Ro) and macrophages (CD68). The inflammation, apoptosis, necrosis and fibrosis were investigated by ELISA, chemiluminescent, immunohistochemical and histological assays. RESULTS: The pro-inflammatory cytokine IL-6 was significantly elevated in iDCM sera (3.3 vs. 10.98 μg/ml; P < 0.05). Sera levels of caspase-9, −8 and −3 had increased 6.24-, 3.1- and 3.62-fold, (P < 0.05) and only slightly (1.3-, 1.22- and 1.03-fold) in biopsies. Significant release of Hsp60 in sera (0.0419 vs. 0.36 ng/mg protein; P < 0.05) suggested a mechanistic involvement of mitochondria in cardiomyocyte apoptosis. The significant MMP9/TIMP1 upregulation in biopsies (0.1931 - 0.476, P < 0.05) and correlation with apoptosis markers show its involvement in initiation of cell death and ECM degradation. A slight activation of the extrinsic apoptotic pathway and the release of hsTnT might support the progression of chronic iDCM. CONCLUSIONS: Data of this study show that significant increase of IL-6, MMP9/TIMP1 and caspases-9, −8, −3 in sera corresponds to molecular mechanisms dominating in chronic iDCM myocardium. The initial apoptotic pathway was more activated by the intramyocardial inflammation and might be associated with extrinsic apoptotic pathway through the pro-apoptotic Bax. The activated intrinsic form of myocardial apoptosis, absence of necrosis and decreased fibrosis are most typical characteristics of chronic iDCM. Clinical use of anti-inflammatory drugs together with specific anti-apoptotic treatment might improve the efficiency of therapies against chronic iDCM before heart failure occurs. BioMed Central 2015-03-26 /pmc/articles/PMC4466865/ /pubmed/25888309 http://dx.doi.org/10.1186/s12872-015-0017-1 Text en © Bironaite et al. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Bironaite, Daiva
Daunoravicius, Dainius
Bogomolovas, Julius
Cibiras, Sigitas
Vitkus, Dalius
Zurauskas, Edvardas
Zasytyte, Ieva
Rucinskas, Kestutis
Labeit, Siegfried
Venalis, Algirdas
Grabauskiene, Virginija
Molecular mechanisms behind progressing chronic inflammatory dilated cardiomyopathy
title Molecular mechanisms behind progressing chronic inflammatory dilated cardiomyopathy
title_full Molecular mechanisms behind progressing chronic inflammatory dilated cardiomyopathy
title_fullStr Molecular mechanisms behind progressing chronic inflammatory dilated cardiomyopathy
title_full_unstemmed Molecular mechanisms behind progressing chronic inflammatory dilated cardiomyopathy
title_short Molecular mechanisms behind progressing chronic inflammatory dilated cardiomyopathy
title_sort molecular mechanisms behind progressing chronic inflammatory dilated cardiomyopathy
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4466865/
https://www.ncbi.nlm.nih.gov/pubmed/25888309
http://dx.doi.org/10.1186/s12872-015-0017-1
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