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Inhibition of SREBP Improves Cardiac Lipidopathy, Improves Endoplasmic Reticulum Stress, and Modulates Chronic Chagas Cardiomyopathy

BACKGROUND: Trypanosoma cruzi is an intracellular parasite that causes debilitating chronic Chagas cardiomyopathy (CCM), for which there is no effective drug or vaccine. Previously, we demonstrated increased cardiac lipid accumulation and endoplasmic reticulum stress in mice with CCM. Increased endo...

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Autores principales: Ayyappan, Janeesh Plakkal, Lizardo, Kezia, Wang, Sean, Yurkow, Edward, Nagajyothi, Jyothi F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033903/
https://www.ncbi.nlm.nih.gov/pubmed/31973605
http://dx.doi.org/10.1161/JAHA.119.014255
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author Ayyappan, Janeesh Plakkal
Lizardo, Kezia
Wang, Sean
Yurkow, Edward
Nagajyothi, Jyothi F.
author_facet Ayyappan, Janeesh Plakkal
Lizardo, Kezia
Wang, Sean
Yurkow, Edward
Nagajyothi, Jyothi F.
author_sort Ayyappan, Janeesh Plakkal
collection PubMed
description BACKGROUND: Trypanosoma cruzi is an intracellular parasite that causes debilitating chronic Chagas cardiomyopathy (CCM), for which there is no effective drug or vaccine. Previously, we demonstrated increased cardiac lipid accumulation and endoplasmic reticulum stress in mice with CCM. Increased endoplasmic reticulum stress may lead to uncontrolled SREBP (sterol regulatory element‐binding protein) activation and lipotoxicity in the myocardium during the intermediate stage of infection and result in progression to chronic CCM. Therefore, we investigated whether inhibiting SREBP activation modulates CCM progression in T cruzi–infected mice. METHODS AND RESULTS: T cruzi–infected cultured cardiomyocytes (3:1 multiplicity of infection; 24 hours postinfection) were incubated with betulin (3 μmol/L per mL), an SREBP inhibitor, for 24 hours. Quantitative polymerase chain reaction and Western blotting analyses demonstrated a significant reduction in SREBP activation, lipid biosynthesis, and endoplasmic reticulum stress in betulin‐treated infected cells compared with untreated cells. T cruzi infected (10(3) trypomastigotes of the Brazil strain) Swiss mice were fed a customized diet containing betulin during the intermediate stage (40 days postinfection) until the chronic stage (120 DPI). Cardiac ultrasound imaging and histological and biochemical analyses demonstrated anatomical and functional improvements in betulin‐treated, infected mice compared with untreated controls: we observed a significant reduction in cholesterol/fatty acid synthesis that may result in the observed cardiac reduction in cardiac lipid accumulation, mitochondrial and endoplasmic reticulum stress, and ventricular enlargement. CONCLUSIONS: Our study (in vitro and vivo) demonstrates that inhibition of cardiac SREBP activation reduces cardiac damage during T cruzi infection and modulates CCM in a murine Chagas model.
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spelling pubmed-70339032020-02-27 Inhibition of SREBP Improves Cardiac Lipidopathy, Improves Endoplasmic Reticulum Stress, and Modulates Chronic Chagas Cardiomyopathy Ayyappan, Janeesh Plakkal Lizardo, Kezia Wang, Sean Yurkow, Edward Nagajyothi, Jyothi F. J Am Heart Assoc Original Research BACKGROUND: Trypanosoma cruzi is an intracellular parasite that causes debilitating chronic Chagas cardiomyopathy (CCM), for which there is no effective drug or vaccine. Previously, we demonstrated increased cardiac lipid accumulation and endoplasmic reticulum stress in mice with CCM. Increased endoplasmic reticulum stress may lead to uncontrolled SREBP (sterol regulatory element‐binding protein) activation and lipotoxicity in the myocardium during the intermediate stage of infection and result in progression to chronic CCM. Therefore, we investigated whether inhibiting SREBP activation modulates CCM progression in T cruzi–infected mice. METHODS AND RESULTS: T cruzi–infected cultured cardiomyocytes (3:1 multiplicity of infection; 24 hours postinfection) were incubated with betulin (3 μmol/L per mL), an SREBP inhibitor, for 24 hours. Quantitative polymerase chain reaction and Western blotting analyses demonstrated a significant reduction in SREBP activation, lipid biosynthesis, and endoplasmic reticulum stress in betulin‐treated infected cells compared with untreated cells. T cruzi infected (10(3) trypomastigotes of the Brazil strain) Swiss mice were fed a customized diet containing betulin during the intermediate stage (40 days postinfection) until the chronic stage (120 DPI). Cardiac ultrasound imaging and histological and biochemical analyses demonstrated anatomical and functional improvements in betulin‐treated, infected mice compared with untreated controls: we observed a significant reduction in cholesterol/fatty acid synthesis that may result in the observed cardiac reduction in cardiac lipid accumulation, mitochondrial and endoplasmic reticulum stress, and ventricular enlargement. CONCLUSIONS: Our study (in vitro and vivo) demonstrates that inhibition of cardiac SREBP activation reduces cardiac damage during T cruzi infection and modulates CCM in a murine Chagas model. John Wiley and Sons Inc. 2020-01-24 /pmc/articles/PMC7033903/ /pubmed/31973605 http://dx.doi.org/10.1161/JAHA.119.014255 Text en © 2020 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Research
Ayyappan, Janeesh Plakkal
Lizardo, Kezia
Wang, Sean
Yurkow, Edward
Nagajyothi, Jyothi F.
Inhibition of SREBP Improves Cardiac Lipidopathy, Improves Endoplasmic Reticulum Stress, and Modulates Chronic Chagas Cardiomyopathy
title Inhibition of SREBP Improves Cardiac Lipidopathy, Improves Endoplasmic Reticulum Stress, and Modulates Chronic Chagas Cardiomyopathy
title_full Inhibition of SREBP Improves Cardiac Lipidopathy, Improves Endoplasmic Reticulum Stress, and Modulates Chronic Chagas Cardiomyopathy
title_fullStr Inhibition of SREBP Improves Cardiac Lipidopathy, Improves Endoplasmic Reticulum Stress, and Modulates Chronic Chagas Cardiomyopathy
title_full_unstemmed Inhibition of SREBP Improves Cardiac Lipidopathy, Improves Endoplasmic Reticulum Stress, and Modulates Chronic Chagas Cardiomyopathy
title_short Inhibition of SREBP Improves Cardiac Lipidopathy, Improves Endoplasmic Reticulum Stress, and Modulates Chronic Chagas Cardiomyopathy
title_sort inhibition of srebp improves cardiac lipidopathy, improves endoplasmic reticulum stress, and modulates chronic chagas cardiomyopathy
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033903/
https://www.ncbi.nlm.nih.gov/pubmed/31973605
http://dx.doi.org/10.1161/JAHA.119.014255
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