title: Attenuation of Doxorubicin-induced cardiomyopathy by endothelin-converting enzyme-1 ablation through prevention of mitochondrial biogenesis impairment.
abstract: 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.
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki, Chuo, 650-0017 Kobe, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Miyagawa
authors.forename: Noriaki
authors.initials: N
authors.lastname: Emoto
authors.forename: Bambang
authors.initials: B
authors.lastname: Widyantoro
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakayama
authors.forename: Keiko
authors.initials: K
authors.lastname: Yagi
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Rikitake
authors.forename: Takashi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Hirata
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D000959:Antihypertensive Agents / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D009202:Cardiomyopathies / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000633:toxicity*; D004452:Echocardiography; D019332:Endothelin-1 / Q000378:metabolism; D000072396:Endothelin-Converting Enzymes; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology*
chemical_list: D000903:Antibiotics, Antineoplastic; D000959:Antihypertensive Agents; D019332:Endothelin-1; D010456:Peptides, Cyclic; D004317:Doxorubicin; D009320:Atrial Natriuretic Factor; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606925:Ece1 protein, mouse; D000072396:Endothelin-Converting Enzymes; D006152:Cyclic GMP; C072247:cyclo(Trp-Asp-Pro-Val-Leu)