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




The Overexpression of Twinkle Helicase Ameliorates the Progression of Cardiac Fibrosis and Heart Failure in Pressure Overload Model in Mice - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

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.



Autor: Atsushi Tanaka, Tomomi Ide , Takeo Fujino, Ken Onitsuka, Masataka Ikeda, Takako Takehara, Yuko Hata, Emil Ylikallio, Henna Tyynis

Fuente: http://plos.srce.hr/



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