Increased myocardial 18F-FDG uptake as a marker of Doxorubicin-induced oxidative stress
Increased myocardial 18F-FDG uptake as a marker of Doxorubicin-induced oxidative stress
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DOI：
10.1007/s12350-019-01618-x
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发表时间：
2020-12-01
影响因子：
2.4
通讯作者：
Marini, Cecilia
中科院分区：
文献类型：
--
作者：
Bauckneht, Matteo;Pastorino, Fabio;Marini, Cecilia
背景氧化应激及其对心肌代谢的干扰在阿霉素（DXR）心脏毒性级联反应中起重要作用。方法小鼠神经母细胞瘤（NB）模型给予5 mg/kg DXR，包括游离DXR、非靶向SLDXR、NB靶向隐形脂质体pep-SLDXR和TP-pep-SLDXR。对照小鼠接受盐水。在基线（PET 1）和治疗后7天（PET 2）进行FDG-PET。PET 2时，评估肌钙蛋白-I和NT-proBNP。取出的心脏进行生化，组织学和免疫组织化学分析。最后，在存在/不存在Free-DXR（1 μ M）的情况下，在培养的H9 c2中同时测量FDG摄取和葡萄糖消耗。结果游离DXR明显增强心肌氧化应激。心肌SUV在对照组和脂质体制剂给药组小鼠中保持相对稳定，而在PET 2时相对于Free-DXR的基线显著增加。在该时间点，心肌SUV与心肌氧化还原应激和己糖-6-磷酸脱氢酶（H6 PD）酶活性直接相关，后者选择性维持细胞抗氧化机制。有趣的是，在体外，Free-DXR选择性地增加FDG提取分数，而不改变葡萄糖的相应值。结论心肌FDG摄取与氧化应激指标之间的直接相关性支持FDG-PET作为DXR氧化损伤的早期生物标志物的潜在作用。
Background Oxidative stress and its interference on myocardial metabolism play a major role in Doxorubicin (DXR) cardiotoxic cascade. Methods Mice models of neuroblastoma (NB) were treated with 5 mg DXR/kg, either free (Free-DXR) or encapsulated in untargeted (SL[DXR]) or in NB-targeting Stealth Liposomes (pep-SL[DXR] and TP-pep-SL[DXR]). Control mice received saline. FDG-PET was performed at baseline (PET1) and 7 days after therapy (PET2). At PET2 Troponin-I and NT-proBNP were assessed. Explanted hearts underwent biochemical, histological, and immunohistochemical analyses. Finally, FDG uptake and glucose consumption were simultaneously measured in cultured H9c2 in the presence/absence of Free-DXR (1 mu M). Results Free-DXR significantly enhanced the myocardial oxidative stress. Myocardial-SUV remained relatively stable in controls and mice treated with liposomal formulations, while it significantly increased at PET2 with respect to baseline in Free-DXR. At this timepoint, myocardial-SUV was directly correlated with both myocardial redox stress and hexose-6-phosphate-dehydrogenase (H6PD) enzymatic activity, which selectively sustain cellular anti-oxidant mechanisms. Intriguingly, in vitro, Free-DXR selectively increased FDG extraction fraction without altering the corresponding value for glucose. Conclusion The direct correlation between cardiac FDG uptake and oxidative stress indexes supports the potential role of FDG-PET as an early biomarker of DXR oxidative damage.