| RRC ID |
44519
|
| 著者 |
Tanaka A, Ide T, Fujino T, Onitsuka K, Ikeda M, Takehara T, Hata Y, Ylikallio E, Tyynismaa H, Suomalainen A, Sunagawa K.
|
| タイトル |
The overexpression of Twinkle helicase ameliorates the progression of cardiac fibrosis and heart failure in pressure overload model in mice.
|
| ジャーナル |
PLoS One
|
| 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.
|
| 巻・号 |
8(6)
|
| ページ |
e67642
|
| 公開日 |
2013-1-1
|
| DOI |
10.1371/journal.pone.0067642
|
| PII |
PONE-D-13-07705
|
| PMID |
23840758
|
| PMC |
PMC3695923
|
| MeSH |
Animals
Aorta / pathology
Constriction
DNA Copy Number Variations / genetics
DNA Helicases / genetics*
Disease Models, Animal
Disease Progression
Echocardiography / methods
Fibrosis / genetics
Fibrosis / pathology*
Gene Expression / genetics*
Heart
Heart Failure / genetics
Heart Failure / pathology*
Hypertrophy, Left Ventricular / genetics
Hypertrophy, Left Ventricular / pathology
Male
Mice
Mice, Transgenic / genetics
Mitochondrial Proteins / genetics*
Pressure
Ventricular Function, Left / genetics
Ventricular Remodeling / genetics
|
| IF |
2.74
|
| 引用数 |
5
|
|
WOS 分野
|
CARDIAC & CARDIOVASCULAR SYSTEMS
|
| リソース情報 |
| ヒト・動物細胞 |
293(RCB1637) |
