Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI, 48202, USA.
Cardiovasc Drugs Ther. 2018 Aug;32(4):319-328. doi: 10.1007/s10557-018-6805-y.
Abnormalities of MITO dynamics occur in HF and have been implicated in disease progression. This study describes the broad range abnormalities of mitochondrial (MITO) dynamics in Heart Failure with reduced ejection fraction (HF) and evaluates the effects of long-term therapy with elamipretide (ELAM), a MITO-targeting peptide, on these abnormalities.
Studies were performed in left ventricular tissue from dogs and humans with HF, and were compared with tissue from healthy dogs and healthy donor human hearts. Dogs with HF were randomized to 3 months therapy with ELAM or vehicle. The following were evaluated in dog and human hearts: (1) regulators of MITO biogenesis, including endothelial nitric oxide synthase (eNOS), cyclic guanosine monophosphate (cGMP), and peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α, a transcription factor that drives MITO biogenesis); (2) regulators of MITO fission and fusion, including fission-1, dynamin-related protein-1, mitofusion-2, dominant optic atrophy-1, and mitofilin; and (3) determinants of cardiolipin (CL) synthesis and remodeling, including CL synthase-1, tafazzin-1, and acyl-CoA:lysocardiolipin acyltransferase-1.
The study showed decreased levels of eNOS, cGMP, and PGC-1α in HF (dog and human). Increased levels of fission-associated proteins, decreased levels of fusion-associated proteins, decreased mitofilin, and abnormalities of CL synthesis and remodeling were also observed. In all instances, these maladaptations were normalized following long-term therapy with ELAM.
Critical abnormalities of MITO dynamics occur in HF and are normalized following long-term therapy with ELAM. The findings provide support for the continued development of ELAM for the treatment of HF.
MITO 动力学异常发生在 HF 中，并与疾病进展有关。本研究描述了心力衰竭（HF）伴射血分数降低的线粒体（MITO）动力学广泛异常，并评估了靶向 MITO 的肽 Elamipretide（ELAM）的长期治疗对这些异常的影响。
在 HF 的犬和人类左心室组织中进行了研究，并与健康犬和健康供体人心肌组织进行了比较。HF 犬随机接受 3 个月的 ELAM 或载体治疗。在犬和人心肌中评估了以下内容：（1）MITO 生物发生的调节剂，包括内皮型一氧化氮合酶（eNOS）、环鸟苷酸（cGMP）和过氧化物酶体增殖物激活受体γ共激活物 1α（PGC-1α，一种驱动 MITO 生物发生的转录因子）；（2）MITO 分裂和融合的调节剂，包括分裂 1、与 dynamin 相关的蛋白 1、mitofusion-2、显性视神经萎缩 1 和 mitofilin；（3）心磷脂（CL）合成和重塑的决定因素，包括 CL 合酶-1、tafazzin-1 和酰基辅酶 A：lysocardiolipin 酰基转移酶-1。
该研究表明，HF（犬和人）中 eNOS、cGMP 和 PGC-1α 水平降低。还观察到与分裂相关的蛋白水平升高、与融合相关的蛋白水平降低、mitofilin 减少以及 CL 合成和重塑异常。在所有情况下，这些适应性不良在长期接受 ELAM 治疗后均得到纠正。
HF 中发生了严重的 MITO 动力学异常，长期接受 ELAM 治疗后可得到纠正。这些发现为继续开发 ELAM 治疗 HF 提供了支持。
