Palmitoyl-carnitine increases RyR2 oxidation and sarcoplasmic reticulum Ca2+ leak in cardiomyocytes: Role of adenine nucleotide translocase
Palmitoyl-carnitine increases RyR2 oxidation and sarcoplasmic reticulum Ca2+ leak in cardiomyocytes: Role of adenine nucleotide translocase
复制标题
DOI：
10.1016/j.bbadis.2015.01.011
复制
发表时间：
2015-05-01
影响因子：
6.2
通讯作者：
Fauconnier, J.
中科院分区：
文献类型：
--
作者：
Roussel, J.;Thireau, Jerome;Fauconnier, J.
长链脂肪酸与肉毒碱结合并形成长链酰基肉毒碱（LCAC），进入线粒体。它们在线粒体基质中被氧化。LCAC在代谢紊乱如急性心肌缺血、慢性心力衰竭或糖尿病性心肌病下迅速积累。LCAC蓄积与严重心律失常相关，包括室性心动过速或纤维性颤动。因此，我们假设棕榈酰-camitine（PC），改变线粒体功能，导致Ca 2+依赖性心律失常。在C57 B1/6小鼠的离体心肌线粒体中，应用10 μ M PC可降低腺嘌呤核苷酸移位酶（ANT）活性，而不影响线粒体（通透性转换孔（mPTP）开放）。线粒体活性氧（ROS）的生产，在分离的心室心肌细胞中用MitoSOX Red染料测量，在PC应用下显著增加。抑制ANT的bongkrekic酸（20 μ M）阻止PC诱导的线粒体ROS的产生。此外，PC增加2型Ryanodine受体（RyR 2）的氧化，S-亚硝基化和FKBP 12.6从RyR 2的解离，从而增加肌浆网（SR）的Ca 2+泄漏。ANT抑制或抗氧化剂策略（N-乙酰半胱氨酸）防止由PC诱导的SR Ca 2+渗漏、FKBP 12.6消耗和RyR 2氧化/S-亚硝基化。最后，无论是bongkrekic酸和NAC显着减少自发性钙波PC下的发生。总之，这些结果表明，PC的升高扰乱ANT活性和ROS依赖性途径中的Ca 2+处理改变，表明一种新的途径，即改变FA代谢可能有助于在病理生理条件下室性心律失常的发展。(C)2015爱思唯尔B. V.保留所有权利。
Long chain fatty acids bind to carnitine and form long chain acyl carnitine (LCAC), to enter into the mitochondria. They are oxidized in the mitochondrial matrix. LCAC accumulates rapidly under metabolic disorders, such as acute cardiac ischemia, chronic heart failure or diabetic cardiomyopathy. LCAC accumulation is associated with severe cardiac arrhythmia including ventricular tachycardia or fibrillation. We thus hypothesized that palmitoyl-camitine (PC), alters mitochondrial function leading to Ca2+ dependent-arrhythmia. In isolated cardiac mitochondria from C57B1/6 mice, application of 10 mu M PC decreased adenine nucleotide translocase (ANT) activity without affecting mitochondria( permeability transition pore (mPTP) opening. Mitochondrial reactive oxygen species (ROS) production, measured with MitoSOX Red dye in isolated ventricular cardiomyocytes, increased significantly under PC application. Inhibition of ANT by bongkrekic acid (20 mu M) prevented PC-induced mitochondrial ROS production. In addition, PC increased type 2 ryanodine receptor (RyR2) oxidation, S-nitrosylation and dissociation of FKBP12.6 from RyR2, and therefore increased sarcoplasmic reticulum (SR) Ca2+ leak. ANT inhibition or anti-oxidant strategy (N-acetylcysteine) prevented SR Ca2+ leak, FKBP12.6 depletion and RyR2 oxidation/S-nitrosylation induced by PC. Finally, both bongkrekic acid and NAC significantly reduced spontaneous Ca2+ wave occurrences under PC. Altogether, these results suggest that an elevation of PC disturbs ANT activity and alters Ca2+ handling in a ROS-dependent pathway, demonstrating a new pathway whereby altered FA metabolism may contribute to the development of ventricular arrhythmia in pathophysiological conditions. (C) 2015 Elsevier B.V. All rights reserved.