使用 13C 标记的乙酰乙酸盐直接评估肾脏线粒体氧化还原状态。
Direct assessment of renal mitochondrial redox state using hyperpolarized C-acetoacetate.
机构信息
Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, USA.
Division of Nephrology, Department of Medicine, University of California, San Francisco, California, USA.
出版信息
Magn Reson Med. 2018 Apr;79(4):1862-1869. doi: 10.1002/mrm.27054. Epub 2018 Jan 3.
PURPOSE
The purpose of this study was to investigate the hyperpolarized ketone body C-acetoacetate (AcAc) and its conversion to C-β-hydroxybutyrate (βOHB) in vivo, catalyzed by β-hydroxybutyrate dehydrogenase (BDH), as a novel direct marker of mitochondrial redox state.
METHODS
[1,3- C ]AcAc was synthesized by hydrolysis of the ethyl ester, and hyperpolarized via dissolution DNP. Cold storage under basic conditions resulted in sufficient chemical stability for use in hyperpolarized (HP) MRI studies. Polarizations and relaxation times of HP [1,3- C ]AcAc were measured in a clinical 3T MRI scanner, and 8 rats were scanned by dynamic HP C MR spectroscopy of a slab through the kidneys. Four rats were scanned after acute treatment with high dose metformin (125 mg/kg, intravenous), which is known to modulate mitochondrial redox via inhibition of mitochondrial complex I. An additional metformin-treated rat was scanned by abdominal 2D CSI (8 mm × 8 mm).
RESULTS
Polarizations of 7 ± 1% and 7 ± 3%, and T relaxation times of 58 ± 5 s and 52 ± 3 s, were attained at the C and C positions, respectively. Rapid conversion of HP AcAc to βOHB was detected in rat kidney in vivo, via the C label. The product HP βOHB was resolved from closely resonating acetate. Conversion to βOHB was also detected via 2D CSI, in both kidney as well as liver regions. Metformin treatment resulted in a significant increase (40%, P = 0.01) of conversion of HP AcAc to βOHB.
CONCLUSION
Rapid conversion of HP AcAc to βOHB was observed in rat kidney in vivo and is a promising new non-invasive marker of mitochondrial redox state. Magn Reson Med 79:1862-1869, 2018. © 2017 International Society for Magnetic Resonance in Medicine.
目的
本研究旨在探讨活体中酮体 1,3- C -乙酰乙酸盐（AcAc）及其经β-羟丁酸脱氢酶（BDH）转化为 1,3- C -β-羟基丁酸盐（βOHB）的情况，将其作为一种新的线粒体氧化还原状态的直接标记物。
方法
通过水解乙酯合成[1,3- C ]AcAc，并通过溶解 DNP 进行极化。在碱性条件下冷藏可确保足够的化学稳定性，适用于极化（HP）MRI 研究。在临床 3T MRI 扫描仪中测量 HP [1,3- C ]AcAc 的极化率和弛豫时间，并对 8 只大鼠进行肾脏切片的动态 HP 13 C 磁共振波谱扫描。4 只大鼠在给予高剂量二甲双胍（125mg/kg，静脉内）急性处理后进行扫描，已知二甲双胍通过抑制线粒体复合物 I 来调节线粒体氧化还原。另外一只接受二甲双胍治疗的大鼠通过腹部 2D CSI（8mm×8mm）进行扫描。
结果
在 C 和 C 位分别获得 7±1%和 7±3%的极化率，以及 58±5s 和 52±3s 的 T 弛豫时间。在体内，通过 C 标记检测到 HP AcAc 迅速转化为βOHB。HP βOHB 产物与紧密共振的乙酸盐分离。通过 2D CSI，在肾脏和肝脏区域均检测到向βOHB 的转化。二甲双胍治疗导致 HP AcAc 向βOHB 的转化显著增加（40%，P=0.01）。
结论
在体内，我们观察到 HP AcAc 在大鼠肾脏中的快速转化，这是一种有前途的新的线粒体氧化还原状态的非侵入性标记物。磁共振医学杂志 79:1862-1869，2018。©2017 年国际磁共振学会。
Zotero 插件