Electrophysiological Abnormalities in VLCAD Deficient hiPSC-Cardiomyocytes Can Be Improved by Lowering Accumulation of Fatty Acid Oxidation Intermediates
Electrophysiological Abnormalities in VLCAD Deficient hiPSC-Cardiomyocytes Can Be Improved by Lowering Accumulation of Fatty Acid Oxidation Intermediates
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DOI：
10.3390/ijms21072589
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发表时间：
2020-04-01
影响因子：
5.6
通讯作者：
Bezzina, Connie R.
中科院分区：
文献类型：
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作者：
Knottnerus, Suzan J. G.;Mengarelli, Isabella;Bezzina, Connie R.
极长链酰基辅酶A脱氢酶缺乏症（VLCADD）患者可出现危及生命的心律失常。其病理生理机制尚不清楚。我们将来自一名轻度和一名严重受影响的VLCADD患者的成纤维细胞重编程为人类诱导多能干细胞（hiPSC），并将其分化为心肌细胞（VLCADD-CM）。与对照CM相比，VLCADD-CM显示更短的动作电位（AP），更多的延迟后除极（DAD）和更高的收缩期和舒张期细胞内Ca 2+浓度（[Ca 2 +]（i））。线粒体增强剂白藜芦醇减轻了轻度VLCADD-CM的生化、电生理和[Ca 2 +]（i）变化，但在重度VLCADD-CM中没有。脂肪酸氧化的潜在毒性中间体的积累被阻断底物还原与依托莫西。与依托莫司孵育导致两种VLCADD-CM的AP持续时间显著延长，DAD和[Ca 2 +]（i）降低。这些结果提供了令人信服的证据，即减少脂肪酸氧化中间体的积累，无论是通过增加线粒体生物合成（白藜芦醇）增强脂肪酸氧化通量，还是通过抑制脂肪酸转运到线粒体（依托莫西），都可以挽救VLCADD-CM中的促心律失常缺陷，并为新的治疗方法打开大门。
Patients with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) can present with life-threatening cardiac arrhythmias. The pathophysiological mechanism is unknown. We reprogrammed fibroblasts from one mildly and one severely affected VLCADD patient, into human induced pluripotent stem cells (hiPSCs) and differentiated these into cardiomyocytes (VLCADD-CMs). VLCADD-CMs displayed shorter action potentials (APs), more delayed afterdepolarizations (DADs) and higher systolic and diastolic intracellular Ca2+ concentration ([Ca2+](i)) than control CMs. The mitochondrial booster resveratrol mitigated the biochemical, electrophysiological and [Ca2+](i) changes in the mild but not in the severe VLCADD-CMs. Accumulation of potentially toxic intermediates of fatty acid oxidation was blocked by substrate reduction with etomoxir. Incubation with etomoxir led to marked prolongation of AP duration and reduced DADs and [Ca2+](i) in both VLCADD-CMs. These results provide compelling evidence that reduced accumulation of fatty acid oxidation intermediates, either by enhanced fatty acid oxidation flux through increased mitochondria biogenesis (resveratrol) or by inhibition of fatty acid transport into the mitochondria (etomoxir), rescues pro-arrhythmia defects in VLCADD-CMs and open doors for new treatments.