Abstract 3285: Attenuation of Doxorubicin-Induced Cardiomyopathy in Endothelin Converting Enzyme-1 Heterozygous Knockout Mice Through Preventing the Impairment of Cardiac Mitochondrial Biogenesis
[Background] Doxorubicin is an effective anticancer drug and frequently used in the treatment of hematological and solid tumors, but the clinical benefit is limited by its cardiotoxicity. The inhibition of mitochondrial biogenesis appears to be responsible for the pathogenesis of Doxorubicin-induced cardiomyopathy. Endothelin-1 is a vasoconstrictive peptide and produced from big endothelin-1 by endothelin converting enzyme (ECE). Endothelin-1 is known to be multifunctional peptide, and is upregulated by Doxorubicin. However, the role of the endothelin system in Doxorubicin-induced cardiomyopathy is not fully solved. We investigated the role of the endothelin system in Doxorubicin-induced cardiomyopathy with endothelin converting enzyme-1 heterozygous knockout mice (ECE-1+/− mice).
[Methods] Cardiomyopathy was induced by a single intraperitoneal injection of Doxorubicin (15mg/kg). Five days after treatment, cardiac function, histology, gene expression, cardiac mitochondrial DNA copy number and ATP content of hearts were analyzed.
[Results] Echocardiography revealed that fractional shortening was significantly higher in ECE-1+/− mice than that in control mice (51.1±2.1% vs. control 39.4±3.4%, P<0.05, n=12/group). In histological analysis, the cardiomyocyte size of ECE-1+/− mice was larger (230.4±6.8μm2 vs. control 197.0±7.4μm2, P<0.01, n=9/group), and electron micrographs revealed that the damage of cardiomyocytes was less. Real time RT-PCR analysis demonstrated that PPARγ coactivater 1α, a key regulator of mitochondrial biogenesis, was higher in ECE-1+/− mice (1.3 fold, P<0.05 vs. control, n=9/group). In Doxorubicin-treated hearts of ECE-1+/− mice, the mitochondrial DNA copy number and the ATP content were higher than those of control mice (1.7 fold, P<0.05 vs. control, n=5/group and 6.99±0.48mM/mg heart vs. 5.29±0.27mM/mg heart, P<0.05, n=5/group respectively).
[Conclusions] The inhibition of the endothelin system by decreased ECE-1 expression attenuated Doxorubicin-induced cardiomyopathy via preventing the impairment of cardiac mitochondrial biogenesis. The inhibition of ECE-1 may be a new therapeutic strategy for Doxorubicin-induced cardiomyopathy.