title: The overexpression of Twinkle helicase ameliorates the progression of cardiac fibrosis and heart failure in pressure overload model in mice.
abstract: 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.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tanaka
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ide
authors.forename: Takeo
authors.initials: T
authors.lastname: Fujino
authors.forename: Ken
authors.initials: K
authors.lastname: Onitsuka
authors.forename: Masataka
authors.initials: M
authors.lastname: Ikeda
authors.forename: Takako
authors.initials: T
authors.lastname: Takehara
authors.forename: Yuko
authors.initials: Y
authors.lastname: Hata
authors.forename: Emil
authors.initials: E
authors.lastname: Ylikallio
authors.forename: Henna
authors.initials: H
authors.lastname: Tyynismaa
authors.forename: Anu
authors.initials: A
authors.lastname: Suomalainen
authors.forename: Kenji
authors.initials: K
authors.lastname: Sunagawa
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D003250:Constriction; D056915:DNA Copy Number Variations / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D004452:Echocardiography / Q000379:methods; D005355:Fibrosis / Q000235:genetics / Q000473:pathology*; D015870:Gene Expression / Q000235:genetics*; D006321:Heart; D006333:Heart Failure / Q000235:genetics / Q000473:pathology*; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics*; D011312:Pressure; D016277:Ventricular Function, Left / Q000235:genetics; D020257:Ventricular Remodeling / Q000235:genetics
chemical_list: D024101:Mitochondrial Proteins; C513299:Twnk protein, mouse; D004265:DNA Helicases