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:	Atsushi Tanaka, Tomomi Ide, Takeo Fujino, Ken Onitsuka, Masataka Ikeda, Takako Takehara, Yuko Hata, Emil Ylikallio, Henna Tyynismaa, Anu Suomalainen, Kenji Sunagawa
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/227f0dfbabc440eba3c453847b1c3aff
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spelling	oai:doaj.org-article:227f0dfbabc440eba3c453847b1c3aff2021-11-18T07:39:24ZThe overexpression of Twinkle helicase ameliorates the progression of cardiac fibrosis and heart failure in pressure overload model in mice.1932-620310.1371/journal.pone.0067642https://doaj.org/article/227f0dfbabc440eba3c453847b1c3aff2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23840758/?tool=EBIhttps://doaj.org/toc/1932-6203Myocardial 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.Atsushi TanakaTomomi IdeTakeo FujinoKen OnitsukaMasataka IkedaTakako TakeharaYuko HataEmil YlikallioHenna TyynismaaAnu SuomalainenKenji SunagawaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 6, p e67642 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Atsushi Tanaka Tomomi Ide Takeo Fujino Ken Onitsuka Masataka Ikeda Takako Takehara Yuko Hata Emil Ylikallio Henna Tyynismaa Anu Suomalainen Kenji Sunagawa The overexpression of Twinkle helicase ameliorates the progression of cardiac fibrosis and heart failure in pressure overload model in mice.
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.
format	article
author	Atsushi Tanaka Tomomi Ide Takeo Fujino Ken Onitsuka Masataka Ikeda Takako Takehara Yuko Hata Emil Ylikallio Henna Tyynismaa Anu Suomalainen Kenji Sunagawa
author_facet	Atsushi Tanaka Tomomi Ide Takeo Fujino Ken Onitsuka Masataka Ikeda Takako Takehara Yuko Hata Emil Ylikallio Henna Tyynismaa Anu Suomalainen Kenji Sunagawa
author_sort	Atsushi Tanaka
title	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_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_sort	overexpression of twinkle helicase ameliorates the progression of cardiac fibrosis and heart failure in pressure overload model in mice.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/227f0dfbabc440eba3c453847b1c3aff
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The overexpression of Twinkle helicase ameliorates the progression of cardiac fibrosis and heart failure in pressure overload model in mice.

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