Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki, Chuo, 650-0017 Kobe, Japan.
Hypertension. 2010 Mar;55(3):738-46. doi: 10.1161/HYPERTENSIONAHA.109.141903. Epub 2010 Jan 25.
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.
多柔比星是一种有效的抗肿瘤药物;然而,其临床获益受到其心脏毒性的限制。线粒体生物发生的抑制是导致多柔比星诱导性心肌病的发病机制。内皮素-1 是一种由内皮素转换酶-1(ECE-1)从大内皮素-1 产生的血管收缩肽,是一种多功能肽。虽然接受多柔比星治疗的患者的血浆内皮素-1 水平升高,但 ECE-1 抑制对多柔比星诱导性心肌病的影响尚不清楚。通过单次腹腔注射多柔比星(15mg/kg)诱导心肌病。治疗后 5 天,评估心脏功能、组织学变化和线粒体生物发生。超声心动图显示,与 ECE-1 杂合子敲除(ECE-1(+/-))小鼠相比,多柔比星处理的野生型(ECE-1(+/+))小鼠的心脏收缩功能明显恶化。在组织学分析中,ECE-1(+/-)小鼠的心肌细胞大小较大,心肌细胞损伤较少。与 ECE-1(+/-)小鼠相比,ECE-1(+/+)小鼠的组织三磷酸腺苷含量和线粒体超氧化物歧化酶减少,活性氧生成增加。ECE-1(+/+)小鼠的心脏线粒体脱氧核糖核酸拷贝数和线粒体生物发生关键调节因子的表达减少。ECE-1(+/-)小鼠的心脏 cGMP 含量和血清心钠肽浓度增加。总之,ECE-1 的抑制通过抑制心脏线粒体生物发生的损伤减轻了多柔比星诱导的心肌病。这主要是由于内皮素-1 水平降低和增强的利钠肽-cGMP 途径引起的。因此,ECE-1 的抑制可能是多柔比星诱导性心肌病的一种新的治疗策略。