Electrophysiological Abnormalities in VLCAD Deficient hiPSC-Cardiomyocytes Can Be Improved by Lowering Accumulation of Fatty Acid Oxidation Intermediates.

• 影响指数: 6.208
• 发表时间: Apr 2020 8
• 来源期刊: Int J Mol Sci
• DOI: 10.3390/ijms21072589
• PMID: 32276429
• 文章类型: Journal Article
• 中科院分区: Q2
• 方向: 生物
• 作者列表: Knottnerus SJG,Mengarelli I,Wüst RCI,Baartscheer A,Bleeker JC,Coronel R,Ferdinandusse S,Guan K,IJlst L,Li W,Luo X,Portero VM,Ulbricht Y,Visser G,Wanders RJA,Wijburg FA,Verkerk AO,Houtkooper RH,Bezzina CR

关键词: VLCADD; acylcarnitines; arrhythmias; hiPSC

Mesh: Action Potentials; Acyl-CoA Dehydrogenase, Long-Chain / deficiency; Arrhythmias, Cardiac / etiology prevention & control; Cardiac Electrophysiology; Congenital Bone Marrow Failure Syndromes / complications physiopathology; Epoxy Compounds / pharmacology; Fatty Acids / chemistry metabolism; Humans; Induced Pluripotent Stem Cells; Lipid Metabolism, Inborn Errors / complications physiopathology; Mitochondria / physiology; Mitochondrial Diseases / complications physiopathology; Muscular Diseases / complications physiopathology; Myocytes, Cardiac / drug effects physiology; Oxidation-Reduction; Resveratrol / pharmacology

Abstract

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.