Attenuation of doxorubicin-induced cardiomyopathy by endothelin-converting enzyme-1 ablation through prevention of mitochondrial biogenesis impairment

Kazuya Miyagawa, Noriaki Emoto, Bambang Widyantoro, Kazuhiko Nakayama, Keiko Yagi, Yoshiyuki Rikitake, Takashi Suzuki, Ken Ichi Hirata

研究成果: Article査読

26 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)738-746
ページ数9
ジャーナルHypertension
55
3
DOI
出版ステータスPublished - 2010 3
外部発表はい

ASJC Scopus subject areas

  • 内科学

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