Cardiovascular Research Centre, Department of Pediatrics, Mazankowski Alberta Heart Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada; Division of Cardiac Surgery, Department of Surgery, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
J Mol Cell Cardiol. 2013 Oct;63:180-8. doi: 10.1016/j.yjmcc.2013.07.020. Epub 2013 Aug 12.
Although pre-clinical evidence has suggested that partial inhibition of myocardial fatty acid oxidation (FAO) and subsequent switch to greater glucose oxidation for ATP production can prevent ischemia/reperfusion injury, controversy about this approach persists. For example, mice with germline deletion of the FA transporter CD36, exhibited either impaired or unchanged post-ischemic functional recovery despite a 40-60% reduction in FAO rates. Because there are limitations to cardiac studies utilizing whole body CD36 knockout (totalCD36KO) mice, we have now generated an inducible and cardiomyocyte-specific CD36 KO (icCD36KO) mouse to better address the role of cardiomyocyte CD36 and its regulation of FAO and post-ischemic functional recovery. Four to six weeks following CD36 ablation, hearts from icCD36KO mice had significantly decreased FA uptake compared to controls, which was paralleled by significant reductions in intramyocardial triacylglycerol content. Analysis of cardiac energy metabolism using ex vivo working heart perfusions showed that reduced FAO rates were compensated by enhanced glucose oxidation in the hearts from icCD36KO mice. In contrast to the totalCD36KO mice, hearts from icCD36KO mice exhibited significantly improved functional recovery following ischemia/reperfusion (18min of global no-flow ischemia followed by 40min of aerobic reperfusion). This improved recovery was associated with lower calculated proton production prior to and following ischemia compared to controls. Moreover, the amount of ATP generated relative to cardiac work was significantly lower in the hearts from icCD36KO mice compared to controls, indicating significantly increased cardiac efficiency in the hearts from icCD36KO mice. These data provide genetic evidence that reduced FAO as a result of diminished CD36-mediated FA uptake improves post-ischemic cardiac efficiency and functional recovery. As such, targeting cardiomyocyte FA uptake and FAO via inhibition of CD36 in the adult myocardium may provide therapeutic benefit during ischemia-reperfusion.
尽管临床前证据表明，部分抑制心肌脂肪酸氧化（FAO）并随后切换为更大的葡萄糖氧化以产生 ATP 可以预防缺血/再灌注损伤，但对此方法仍存在争议。例如，尽管 FA 转运蛋白 CD36 的种系缺失小鼠的 FAO 率降低了 40-60%，但其缺血后功能恢复要么受损，要么不变。由于利用全身 CD36 敲除（totalCD36KO）小鼠进行心脏研究存在局限性，我们现在已经生成了一种可诱导的和心肌细胞特异性的 CD36 敲除（icCD36KO）小鼠，以更好地解决心肌细胞 CD36 的作用及其对 FAO 和缺血后功能恢复的调节。在 CD36 消融后 4 到 6 周，icCD36KO 小鼠的心脏与对照组相比，FA 摄取显著减少，这与心肌内三酰基甘油含量的显著减少相平行。使用离体工作心脏灌注分析心脏能量代谢表明，icCD36KO 小鼠心脏的 FAO 率降低被增强的葡萄糖氧化所补偿。与 totalCD36KO 小鼠不同，icCD36KO 小鼠的心脏在缺血/再灌注后表现出显著改善的功能恢复（40min 有氧再灌注）。这种改善的恢复与与对照组相比，缺血前和缺血后计算出的质子产生量较低有关。此外，与对照组相比，icCD36KO 小鼠心脏中生成的与心脏工作相关的 ATP 量显著降低，表明 icCD36KO 小鼠心脏的心脏效率显著提高。这些数据提供了遗传证据，表明由于 CD36 介导的 FA 摄取减少而导致的 FAO 减少可改善缺血后心脏效率和功能恢复。因此，在成年心肌中通过抑制 CD36 靶向心肌细胞 FA 摄取和 FAO 可能在缺血/再灌注期间提供治疗益处。
