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The Overexpression of Twinkle Helicase Ameliorates the Progression of Cardiac Fibrosis and Heart Failure in Pressure Overload Model in Mice

Myocardial mitochondrial DNA (mtDNA) copy number decreases in heart failure. In post-myocardial infarction mice, increasing mtDNA copy number by overexpressing mitochondrial transcription factor attenuates mtDNA deficiency and ameliorates pathological remodeling thereby markedly improving survival....

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Autores principales: Tanaka, Atsushi, Ide, Tomomi, Fujino, Takeo, Onitsuka, Ken, Ikeda, Masataka, Takehara, Takako, Hata, Yuko, Ylikallio, Emil, Tyynismaa, Henna, Suomalainen, Anu, Sunagawa, Kenji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3695923/
https://www.ncbi.nlm.nih.gov/pubmed/23840758
http://dx.doi.org/10.1371/journal.pone.0067642
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author Tanaka, Atsushi
Ide, Tomomi
Fujino, Takeo
Onitsuka, Ken
Ikeda, Masataka
Takehara, Takako
Hata, Yuko
Ylikallio, Emil
Tyynismaa, Henna
Suomalainen, Anu
Sunagawa, Kenji
author_facet Tanaka, Atsushi
Ide, Tomomi
Fujino, Takeo
Onitsuka, Ken
Ikeda, Masataka
Takehara, Takako
Hata, Yuko
Ylikallio, Emil
Tyynismaa, Henna
Suomalainen, Anu
Sunagawa, Kenji
author_sort Tanaka, Atsushi
collection PubMed
description Myocardial mitochondrial DNA (mtDNA) copy number decreases in heart failure. In post-myocardial infarction mice, increasing mtDNA copy number by overexpressing mitochondrial transcription factor attenuates mtDNA deficiency and ameliorates pathological remodeling thereby markedly improving survival. However, the functional significance of increased mtDNA copy number in hypertensive heart disease remains unknown. We addressed this question using transgenic mice that overexpress Twinkle helicase (Twinkle; Tg), the mtDNA helicase, and examined whether Twinkle overexpression protects the heart from left ventricular (LV) remodeling and failure after pressure overload created by transverse aortic constriction (TAC). Twinkle overexpression increased mtDNA copy number by 2.2±0.1-fold. Heart weight, LV diastolic volume and wall thickness were comparable between Tg and wild type littermates (WT) at 28 days after TAC operation. LV end-diastolic pressure increased in WT after TAC (8.6±2.8 mmHg), and this increase was attenuated in Tg (4.6±2.6 mmHg). Impaired LV fractional shortening after TAC operation was also suppressed in Tg, as measured by echocardiography (WT: 16.2±7.2% vs Tg: 20.7±6.2%). These LV functional improvements were accompanied by a decrease in interstitial fibrosis (WT: 10.6±1.1% vs Tg: 3.0±0.6%). In in vitro studies, overexpressing Twinkle using an adenovirus vector in cultured cardiac fibroblasts significantly suppressed mRNA of collagen 1a, collagen 3a and connective tissue growth factor, and angiotensin II-induced transforming growth factor β1 expression. The findings suggest that Twinkle overexpression prevents LV function deterioration. In conclusion, Twinkle overexpression increases mtDNA copy number and ameliorates the progression of LV fibrosis and heart failure in a mouse pressure overload model. Increasing mtDNA copy number by Twinkle overexpression could be a novel therapeutic strategy for hypertensive heart disease.
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spelling pubmed-36959232013-07-09 The Overexpression of Twinkle Helicase Ameliorates the Progression of Cardiac Fibrosis and Heart Failure in Pressure Overload Model in Mice Tanaka, Atsushi Ide, Tomomi Fujino, Takeo Onitsuka, Ken Ikeda, Masataka Takehara, Takako Hata, Yuko Ylikallio, Emil Tyynismaa, Henna Suomalainen, Anu Sunagawa, Kenji PLoS One Research Article Myocardial mitochondrial DNA (mtDNA) copy number decreases in heart failure. In post-myocardial infarction mice, increasing mtDNA copy number by overexpressing mitochondrial transcription factor attenuates mtDNA deficiency and ameliorates pathological remodeling thereby markedly improving survival. However, the functional significance of increased mtDNA copy number in hypertensive heart disease remains unknown. We addressed this question using transgenic mice that overexpress Twinkle helicase (Twinkle; Tg), the mtDNA helicase, and examined whether Twinkle overexpression protects the heart from left ventricular (LV) remodeling and failure after pressure overload created by transverse aortic constriction (TAC). Twinkle overexpression increased mtDNA copy number by 2.2±0.1-fold. Heart weight, LV diastolic volume and wall thickness were comparable between Tg and wild type littermates (WT) at 28 days after TAC operation. LV end-diastolic pressure increased in WT after TAC (8.6±2.8 mmHg), and this increase was attenuated in Tg (4.6±2.6 mmHg). Impaired LV fractional shortening after TAC operation was also suppressed in Tg, as measured by echocardiography (WT: 16.2±7.2% vs Tg: 20.7±6.2%). These LV functional improvements were accompanied by a decrease in interstitial fibrosis (WT: 10.6±1.1% vs Tg: 3.0±0.6%). In in vitro studies, overexpressing Twinkle using an adenovirus vector in cultured cardiac fibroblasts significantly suppressed mRNA of collagen 1a, collagen 3a and connective tissue growth factor, and angiotensin II-induced transforming growth factor β1 expression. The findings suggest that Twinkle overexpression prevents LV function deterioration. In conclusion, Twinkle overexpression increases mtDNA copy number and ameliorates the progression of LV fibrosis and heart failure in a mouse pressure overload model. Increasing mtDNA copy number by Twinkle overexpression could be a novel therapeutic strategy for hypertensive heart disease. Public Library of Science 2013-06-28 /pmc/articles/PMC3695923/ /pubmed/23840758 http://dx.doi.org/10.1371/journal.pone.0067642 Text en © 2013 Tanaka et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Tanaka, Atsushi
Ide, Tomomi
Fujino, Takeo
Onitsuka, Ken
Ikeda, Masataka
Takehara, Takako
Hata, Yuko
Ylikallio, Emil
Tyynismaa, Henna
Suomalainen, Anu
Sunagawa, Kenji
The Overexpression of Twinkle Helicase Ameliorates the Progression of Cardiac Fibrosis and Heart Failure in Pressure Overload Model in Mice
title The Overexpression of Twinkle Helicase Ameliorates the Progression of Cardiac Fibrosis and Heart Failure in Pressure Overload Model in Mice
title_full The Overexpression of Twinkle Helicase Ameliorates the Progression of Cardiac Fibrosis and Heart Failure in Pressure Overload Model in Mice
title_fullStr The Overexpression of Twinkle Helicase Ameliorates the Progression of Cardiac Fibrosis and Heart Failure in Pressure Overload Model in Mice
title_full_unstemmed The Overexpression of Twinkle Helicase Ameliorates the Progression of Cardiac Fibrosis and Heart Failure in Pressure Overload Model in Mice
title_short The Overexpression of Twinkle Helicase Ameliorates the Progression of Cardiac Fibrosis and Heart Failure in Pressure Overload Model in Mice
title_sort overexpression of twinkle helicase ameliorates the progression of cardiac fibrosis and heart failure in pressure overload model in mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3695923/
https://www.ncbi.nlm.nih.gov/pubmed/23840758
http://dx.doi.org/10.1371/journal.pone.0067642
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