☆ 4.7 Article

Attenuation of Doxorubicin-Induced Cardiomyopathy by Endothelin-Converting Enzyme-1 Ablation Through Prevention of Mitochondrial Biogenesis Impairment

HYPERTENSION (2010)

期刊

HYPERTENSION

卷 55, 期 3, 页码 738-U67

出版社

LIPPINCOTT WILLIAMS & WILKINS

DOI: 10.1161/HYPERTENSIONAHA.109.141903

关键词

cardiomyopathy; doxorubicin; endothelin-converting enzyme-1; mitochondria; endothelin-1; atrial natriuretic peptide

类别

Peripheral Vascular Disease

资金

Japan Society for the Promotion of Science

向作者/读者索取更多资源

Protocol

社区支持

Reagent

社区支持

摘要

Doxorubicin is an effective antineoplastic drug; however, its clinical benefit is limited by its cardiotoxicity. The inhibition of mitochondrial biogenesis is responsible for the pathogenesis of doxorubicin-induced cardiomyopathy. Endothelin-1 is a vasoconstrictive peptide produced from big endothelin-1 by endothelin-converting enzyme-1 (ECE-1) and a multifunctional peptide. Although plasma endothelin-1 levels are elevated in patients treated with doxorubicin, the effect of ECE-1 inhibition on doxorubicin-induced cardiomyopathy is not understood. Cardiomyopathy was induced by a single IP injection of doxorubicin (15 mg/kg). Five days after treatment, cardiac function, histological change, and mitochondrial biogenesis were assessed. Echocardiography revealed that cardiac systolic function was significantly deteriorated in doxorubicin-treated wild-type (ECE-1(+/-)) mice compared with ECE-1 heterozygous knockout (ECE-1(+/-)) mice. In histological analysis, cardiomyocyte size in ECE-1(+/-) mice was larger, and cardiomyocyte damage was less. In ECE-1(+/+) mice, tissue adenosine triphosphate content and mitochondrial superoxide dismutase were decreased, and reactive oxygen species generation was increased compared with ECE-1(+/-) mice. Cardiac mitochondrial deoxyribonucleic acid copy number and expressions of key regulators for mitochondrial biogenesis were decreased in ECE-1(+/+) mice. Cardiac cGMP content and serum atrial natriuretic peptide concentration were increased in ECE-1(+/+) mice. In conclusion, the inhibition of ECE-1 attenuated doxorubicin-induced cardiomyopathy by inhibiting the impairment of cardiac mitochondrial biogenesis. This was mainly induced by decreased endothelin-1 levels and an enhanced atrial natriuretic peptide-cGMP pathway. Thus, the inhibition of ECE-1 may be a new therapeutic strategy for doxorubicin-induced cardiomyopathy. (Hypertension. 2010; 55: 738-746.)

作者

我是这篇论文的作者

点击您的名字以认领此论文并将其添加到您的个人资料中。

主要评分

4.7

评分不足

次要评分

新颖性

重要性

科学严谨性

评价这篇论文

proANP Metabolism Provides New Insights Into Sacubitril/Valsartan Mode of Action

Thibault Michel, Helene Nougue, Jerome Cartailler, Guillaume Lefevre, Malha Sadoune, Francois Picard, Alain Cohen-Solal, Damien Logeart, Jean-Marie Launay, Nicolas Vodovar

Summary: Sacubitril/valsartan (S/V) treatment can increase plasma ANP levels in patients with heart failure with reduced ejection fraction (HFrEF) through multiple mechanisms, involving the regulation of miR-425 and miR1-3p, as well as partial inhibition of ECE1 and ANPEP. The glycosylation of proANP can interfere with the measurement of plasma ANP levels.

CIRCULATION RESEARCH (2022)