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Topoisomerase 2B Decrease Results in Diastolic Dysfunction via p53 and Akt: A Novel Pathway

Diastolic dysfunction is condition of a stiff ventricle and a function of aging. It causes significant cardiovascular mortality and morbidity, and in fact, three million Americans are currently suffering from this condition. To date, all the pharmacological clinical trials have been negative. The la...

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Autores principales: Moudgil, Rohit, Samra, Gursharan, Ko, Kyung Ae, Vu, Hang Thi, Thomas, Tamlyn N., Luo, Weijia, Chang, Jiang, Reddy, Anilkumar K., Fujiwara, Keigi, Abe, Jun-ichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709875/
https://www.ncbi.nlm.nih.gov/pubmed/33330654
http://dx.doi.org/10.3389/fcvm.2020.594123
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author Moudgil, Rohit
Samra, Gursharan
Ko, Kyung Ae
Vu, Hang Thi
Thomas, Tamlyn N.
Luo, Weijia
Chang, Jiang
Reddy, Anilkumar K.
Fujiwara, Keigi
Abe, Jun-ichi
author_facet Moudgil, Rohit
Samra, Gursharan
Ko, Kyung Ae
Vu, Hang Thi
Thomas, Tamlyn N.
Luo, Weijia
Chang, Jiang
Reddy, Anilkumar K.
Fujiwara, Keigi
Abe, Jun-ichi
author_sort Moudgil, Rohit
collection PubMed
description Diastolic dysfunction is condition of a stiff ventricle and a function of aging. It causes significant cardiovascular mortality and morbidity, and in fact, three million Americans are currently suffering from this condition. To date, all the pharmacological clinical trials have been negative. The lack of success in attenuating/ameliorating diastolic dysfunction stems from lack of duplication of myriads of clinical manifestation in pre-clinical settings. Here we report, a novel genetically engineered mice which may represents a preclinical model of human diastolic dysfunction to some extent. Topoisomerase 2 beta (Top2b) is an important enzyme in transcriptional activation of some inducible genes through transient double-stranded DNA breakage events around promoter regions. We created a conditional, tissue-specific, inducible Top2b knockout mice in the heart. Serendipitously, echocardiographic parameters and more invasive analysis of left ventricular function with pressure–volume loops show features of diastolic dysfunction. This was also confirmed histologically. At the cellular level, the Top2b knockdown showed morphological changes and molecular signaling akin to human diastolic dysfunction. Reverse phase protein analysis showed activation of p53 and inhibition of, Akt, as the possible mediators of diastolic dysfunction. Finally, activation of p53 and inhibition of Akt were confirmed in myocardial biopsy samples obtained from human diastolic dysfunctional hearts. Thus, we report for the first time, a Top2b downregulated preclinical mice model for diastolic dysfunction which demonstrates that Akt and p53 are the possible mediators of the pathology, hence representing novel and viable targets for future therapeutic interventions in diastolic dysfunction.
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spelling pubmed-77098752020-12-15 Topoisomerase 2B Decrease Results in Diastolic Dysfunction via p53 and Akt: A Novel Pathway Moudgil, Rohit Samra, Gursharan Ko, Kyung Ae Vu, Hang Thi Thomas, Tamlyn N. Luo, Weijia Chang, Jiang Reddy, Anilkumar K. Fujiwara, Keigi Abe, Jun-ichi Front Cardiovasc Med Cardiovascular Medicine Diastolic dysfunction is condition of a stiff ventricle and a function of aging. It causes significant cardiovascular mortality and morbidity, and in fact, three million Americans are currently suffering from this condition. To date, all the pharmacological clinical trials have been negative. The lack of success in attenuating/ameliorating diastolic dysfunction stems from lack of duplication of myriads of clinical manifestation in pre-clinical settings. Here we report, a novel genetically engineered mice which may represents a preclinical model of human diastolic dysfunction to some extent. Topoisomerase 2 beta (Top2b) is an important enzyme in transcriptional activation of some inducible genes through transient double-stranded DNA breakage events around promoter regions. We created a conditional, tissue-specific, inducible Top2b knockout mice in the heart. Serendipitously, echocardiographic parameters and more invasive analysis of left ventricular function with pressure–volume loops show features of diastolic dysfunction. This was also confirmed histologically. At the cellular level, the Top2b knockdown showed morphological changes and molecular signaling akin to human diastolic dysfunction. Reverse phase protein analysis showed activation of p53 and inhibition of, Akt, as the possible mediators of diastolic dysfunction. Finally, activation of p53 and inhibition of Akt were confirmed in myocardial biopsy samples obtained from human diastolic dysfunctional hearts. Thus, we report for the first time, a Top2b downregulated preclinical mice model for diastolic dysfunction which demonstrates that Akt and p53 are the possible mediators of the pathology, hence representing novel and viable targets for future therapeutic interventions in diastolic dysfunction. Frontiers Media S.A. 2020-11-06 /pmc/articles/PMC7709875/ /pubmed/33330654 http://dx.doi.org/10.3389/fcvm.2020.594123 Text en Copyright © 2020 Moudgil, Samra, Ko, Vu, Thomas, Luo, Chang, Reddy, Fujiwara and Abe. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cardiovascular Medicine
Moudgil, Rohit
Samra, Gursharan
Ko, Kyung Ae
Vu, Hang Thi
Thomas, Tamlyn N.
Luo, Weijia
Chang, Jiang
Reddy, Anilkumar K.
Fujiwara, Keigi
Abe, Jun-ichi
Topoisomerase 2B Decrease Results in Diastolic Dysfunction via p53 and Akt: A Novel Pathway
title Topoisomerase 2B Decrease Results in Diastolic Dysfunction via p53 and Akt: A Novel Pathway
title_full Topoisomerase 2B Decrease Results in Diastolic Dysfunction via p53 and Akt: A Novel Pathway
title_fullStr Topoisomerase 2B Decrease Results in Diastolic Dysfunction via p53 and Akt: A Novel Pathway
title_full_unstemmed Topoisomerase 2B Decrease Results in Diastolic Dysfunction via p53 and Akt: A Novel Pathway
title_short Topoisomerase 2B Decrease Results in Diastolic Dysfunction via p53 and Akt: A Novel Pathway
title_sort topoisomerase 2b decrease results in diastolic dysfunction via p53 and akt: a novel pathway
topic Cardiovascular Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709875/
https://www.ncbi.nlm.nih.gov/pubmed/33330654
http://dx.doi.org/10.3389/fcvm.2020.594123
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