期刊
CIRCULATION-CARDIOVASCULAR IMAGING
卷 8, 期 2, 页码 -出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCIMAGING.114.001952
关键词
cardiotoxicity; caspase-3; doxorubicin
资金
- Siemens Molecular Imaging
- American Heart Association [11CRP5050015]
- National Institute of Health CTSA [2KL2TR000440]
Background-Anthracycline-induced cardiotoxicity and myocardial dysfunction may be associated with apoptosis. Caspase 3 catalyzes a terminal step in apoptosis, and its expression may serve as a marker of cardiomyocyte apoptosis. We synthesized 18F-CP18, a caspase-3 substrate and evaluated cardiac 18F-CP18 uptake in a mouse model of anthracycline cardiotoxicity. Methods and Results-For 12 weeks, mice were injected with doxorubicin, 3 mg/kg/week, or vehicle (control). Left ventricular fractional shortening was quantified by echocardiography. CP18 uptake after intravenous injection of 250 mu Ci of 18F-CP18, 24 hours post-doxorubicin treatment was quantified by microPET, autoradiography, and gamma counting. Apoptosis was assessed by enzymatic assay of myocardial caspase 3 and TUNEL staining of tissue sections. Compared with controls, at 6 and 12 weeks of doxorubicin treatment, fractional shortening was reduced (20.7%+/- 2.5% versus 31%+/- 3.5%, P=0.010; and 20.3%+/- 3.1% versus 32.4%+/- 2.1%, P=0.011). Doxorubicin treatment was associated with increased 18F-CP18 uptake in % ID/g by gamma counting from 0.36 +/- 0.01 (week 1) to 0.78 +/- 0.01 (week 12), P=0.003. A similar increase in 18F-CP18 uptake was observed by microPET (0.41 +/- 0.04 versus 0.73 +/- 0.1, P=0.014) and autoradiography (1.1 +/- 0.3 versus 2.8 +/- 0.2 P=0.001). Caspase 3 enzymatic activity and apoptosis by TUNEL staining were also increased after 12 weeks of doxorubicin compared with weeks 1 and 3. CP18 uptake in controls was relatively unchanged at weeks 1, 3, and 12. Conclusions-In a mouse model of cardiotoxicity, doxorubicin treatment is associated with increased myocardial caspase 3 expression and an increase in CP18 uptake. 18F-CP18 may be useful for detection of anthracycline-induced myocardial apoptosis.
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