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.
Highlights
Heart failure is the end-stage of various heart conditions and diseases, and has become a major public health problem in most countries. [1,2]
We examined whether Twinkle overexpression protects the heart from left ventricular (LV) remodeling and failure in a mouse pressure overload model created by transverse aortic constriction (TAC)
We first examined the mitochondrial characteristics in Tg and wild type littermates (WT) that were sham-operated or underwent TAC. mitochondrial DNA (mtDNA) copy number increased significantly in Tg compared to WT, both in sham-operated (2.2-fold, P,0.01) and TAC groups (2.9-fold, P,0.01). mtDNA copy number tended to decrease on day 28 after TAC in both WT (P = 0.07 WT-TAC vs. WT-sham) and Tg (P = 0.11, Tg-TAC vs. Tg-sham), the differences were not significant in both groups (Figure 1A)
Summary
Heart failure is the end-stage of various heart conditions and diseases, and has become a major public health problem in most countries. [1,2]. Heart failure is the end-stage of various heart conditions and diseases, and has become a major public health problem in most countries. Hypertension is a common risk factor for heart failure, followed closely by antecedent myocardial infarction. Seventy-five percent of heart failure cases have antecedent hypertension [1]. Hypertension affects approximately one billion people worldwide [3]. Sustained cardiac pressure overload induces cellular, molecular and morphologic remodeling and maladaptations contributing to progressive cardiac dysfunction and heart failure [4]. Except antihypertensive drugs, there is no known effective medical treatment to attenuate pressure overloadinduced cardiac remodeling. New therapeutic strategies to prevent maladaptive remodeling and subsequent progression to heart failure in hypertensive heart disease are highly desirable
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