Doxorubicin Exposure Causes Subacute Cardiac Atrophy Dependent on the Striated Muscle-Specific Ubiquitin Ligase MuRF1
| Autor: | Wei Huang, Ralph B. D'Agostino, W. Gregory Hundley, Cynthia Zhou, Traci L. Parry, Roberto Mota, Sean T Hicks, David I. Brown, Monte S. Willis, Brian C. Jensen, Ju Youn Beak, Jennifer H. Jordan, Melissa C. Caughey, Michael Sola |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
Gene Expression Muscle Proteins 030204 cardiovascular system & hematology Ligases Tripartite Motif Proteins Mice 0302 clinical medicine Anthracyclines Myocytes Cardiac 0303 health sciences Dilated cardiomyopathy Heart Magnetic Resonance Imaging Muscle atrophy Up-Regulation Muscular Atrophy Echocardiography medicine.symptom Cardiology and Cardiovascular Medicine Injections Intraperitoneal medicine.drug Cardiac function curve medicine.medical_specialty Anthracycline Ubiquitin-Protein Ligases Antineoplastic Agents Article 03 medical and health sciences Atrophy Internal medicine medicine Animals Humans Doxorubicin 030304 developmental biology Heart Failure Cardiotoxicity Dose-Response Relationship Drug business.industry Ubiquitin Myocardium medicine.disease Muscle Striated Mice Inbred C57BL Disease Models Animal Endocrinology Heart failure business |
| Zdroj: | Circulation. Heart failure. 12(3) |
| ISSN: | 1941-3297 |
| Popis: | Background Anthracycline chemotherapeutics, such as doxorubicin, are used widely in the treatment of numerous malignancies. The primary dose-limiting adverse effect of anthracyclines is cardiotoxicity that often presents as heart failure due to dilated cardiomyopathy years after anthracycline exposure. Recent data from animal studies indicate that anthracyclines cause cardiac atrophy. The timing of onset and underlying mechanisms are not well defined, and the relevance of these findings to human disease is unclear. Methods and Results Wild-type mice were sacrificed 1 week after intraperitoneal administration of doxorubicin (1–25 mg/kg), revealing a dose-dependent decrease in cardiac mass ( R 2 =0.64; P 2 ; P 2 =0.91; P =0.003) and a molecular profile of muscle atrophy. To investigate the determinants of doxorubicin-induced cardiac atrophy, we administered doxorubicin 20 mg/kg to mice lacking MuRF1 (MuRF1 −/− ) and wild-type littermates. MuRF1 −/− mice were protected from cardiac atrophy and exhibited no reduction in contractile function. To explore the clinical relevance of these findings, we analyzed cardiac magnetic resonance imaging data from 70 patients in the DETECT-1 cohort and found that anthracycline exposure was associated with decreased cardiac mass evident within 1 month and persisting to 6 months after initiation. Conclusions Doxorubicin causes a subacute decrease in cardiac mass in both mice and humans. In mice, doxorubicin-induced cardiac atrophy is dependent on MuRF1. These findings suggest that therapies directed at preventing or reversing cardiac atrophy might preserve the cardiac function of cancer patients receiving anthracyclines. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|