Abstract 76: Ablation of Parkin Attenuates Acute Cardiotoxicity of Doxorubicin Associated with Mitophagy
| Autor: | Chengqun Huang, Allen Andres, Jennifer Ramil, Roberta Gottlieb |
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| Rok vydání: | 2012 |
| Předmět: | |
| Zdroj: | Circulation Research. 111 |
| ISSN: | 1524-4571 0009-7330 |
| Popis: | Parkin is an E3 ubiquitin ligase expressed in heart, skeletal muscle and brain. However, the function of Parkin in the heart is largely unknown. We previously showed in cardiomyocytes and the ischemic heart that Parkin translocates to mitochondria to selectively remove damaged mitochondria through autophagy. It has been shown that Doxorubicin (Dox) induces cardiotoxicity characterized by impaired mitochondrial respiration and energetic failure (PLoS One. 2010; 5:e12733). Here, we investigated the role of Parkin in acute Doxorubicin-induced cardiac dysfunction in mice. Acute cardiotoxicity was induced by IP injection of a single dose of 15 mg/kg Doxorubicin hydrochloride in 10-12 wk-old C57BL/6J (WT) mice and Parkin knock out (PKO) mice matched by age, sex and body weight. Analysis of histology, hemodynamics, and mitochondrial content was performed 7d after Dox. Dox induced significant loss of body weight but less in PKO mice (20% in WT vs 12% in PKO). Dox toxicity was more severe in male mice. Signs of discomfort (decreased mobility and hunched posture) were noted 4d after Dox in 90% of WT male mice vs. 20% of PKO males. Mortality at 7d was 30% in WT mice vs. 10% in PKO mice. Dox caused reduction in heart size to a greater extent (10-20%) in WT than in PKO mice. Significant deterioration of hemodynamics was seen in WT mice 7d after Dox; this was attenuated in PKO mice. Because Parkin mediates mitophagy, we examined autophagy and mitochondrial content 7d in Dox treated hearts. Dox resulted in extensive autophagy and decreased mitochondrial protein content in WT mice; this was attenuated in PKO mice. These results suggest that high-dose Dox triggers extensive Parkin-dependent mitophagy which may contribute to acute cardiac dysfunction. We suggest that therapy directed at the PINK1-Parkin mitophagy pathway may be beneficial in the setting of doxorubicin overdose. |
| Databáze: | OpenAIRE |
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