Background:The FOXO3a (forkhead box O3a)-BNIP3 (B-cell lymphoma 2/adenovirus E1B 19kDa interacting protein 3) pathway modulates mitochondrial dynamics and function and contributes to myocardial remodeling in rodent models of heart failure. We sought to investigate the expression of this pathway along with the expression of mitochondrial biogenesis (PGC-1α [peroxisome proliferator-activated receptor-γ coactivator-1α]), dynamics (DRP-1 [dynamin-related protein 1], OPA-1 [optic atrophy 1], and MFN 2 [mitofusin 2]), and oxidative phosphorylation (citrate synthase and electron transport chain complexes) markers and COX IV (cytochrome C oxidase) activity in myocardium from patients with valvular or ischemic heart disease and heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction (HFrEF).Methods and Results:Subepicardial left ventricular biopsies (10×1×1 mm³) were obtained at aortic valve replacement (HFpEF_AVR, n=5; and HFrEF_AVR, n=4), coronary artery bypass grafting (HFpEF_CABG, n=5; and HFrEF_CABG, n=5), or left ventricular assist device implantation (HFrEF_LVAD, n=4). Subepicardial biopsies from patients with normal left ventricular function (n=2) and from donor hearts (n=3) served as controls (normal). Relative to normal, mitochondrial fragmentation and cristae destruction were evident, and mitochondrial area was decreased in HFpEF; 1.00±0.09 versus 0.71±0.08; P=0.016. These mitochondrial morphological changes were more pronounced in HFrEF (0.54±0.06); P=0.002 HFpEF versus HFrEF. BNIP3 (monomer+dimer) expression was increased in HFpEF (3.99±2.44) and in HFrEF (5.19±1.70) relative to normal; P=0.004 and P<0.001, respectively. However, BNIP3 monomer was increased in HFrEF (4.32±1.43) compared with normal (0.99±0.06) and HFpEF (1.97±0.90); P=0.001 and 0.004, respectively. The HFrEF group uniquely showed increase in DRP-1 expression (1.94±0.38) and decreases in PGC-1α expression (0.61±0.07) and COX IV activity (0.70±0.10) relative to normal; P=0.013, P<0.001, and P<0.001, respectively, with no significant change in electron transport chain complexes expression.Conclusions:These findings in human myocardium confirm studies in rodents where contractile dysfunction is associated with activation of the FOXO3a-BNIP3 pathway and altered mitochondrial dynamics, biogenesis, and function.

中文翻译：

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保留或减少射血分数的人类压力超负荷或缺血性心脏病中的线粒体形态，动力学和功能

背景：FOXO3a（前额箱O3a）-BNIP3（B细胞淋巴瘤2 /腺病毒E1B 19kDa相互作用蛋白3）途径调节线粒体动力学和功能，并在心力衰竭啮齿动物模型中促进心肌重塑。我们试图研究该途径的表达以及线粒体生物发生（PGC-1α[过氧化物酶体增殖物激活的受体-γcoactivator-1α]），动力学（DRP-1 [动力相关蛋白1]，OPA-1）的表达[视神经萎缩1]和MFN 2 [mitofusin 2]），以及患有瓣膜性或缺血性心脏病和心力衰竭患者的心肌中的氧化磷酸化（柠檬酸合酶和电子转运链复合物）标志物和COX IV（细胞色素C氧化酶）活性保留射血分数（HFpEF）或心力衰竭伴射血分数降低（HFrEF）。方法和结果：³）是在主动脉瓣置换术（HFpEF _AVR，n = 5; HFrEF _AVR，n = 4），冠状动脉搭桥术（HFpEF _CABG，n = 5; HFrEF _CABG，n = 5）或左心室辅助下获得的装置植入（HFrEF _LVAD，n = 4）。左心室功能正常的患者（n = 2）和供体心脏的心外膜下活检（n = 3）作为对照（正常）。相对于正常情况，HFpEF的线粒体破碎和destruction破坏明显，线粒体面积减少。1.00±0.09对0.71±0.08; P＝ 0.016。这些线粒体的形态变化在HFrEF中更为明显（0.54±0.06）。P相对于HFrEF = 0.002 HFpEF。与正常相比，HFpEF（3.99±2.44）和HFrEF（5.19±1.70）中的BNIP3（单体+二聚体）表达增加；P分别为0.004和P＜0.001。然而，与正常（0.99±0.06）和HFpEF（1.97±0.90）相比，HFrEF中的BNIP3单体增加（4.32±1.43）；P分别为0.001和0.004。HFrEF组相对于正常组独特地显示DRP-1表达增加（1.94±0.38），PGC-1α表达减少（0.61±0.07）和COX IV活性（0.70±0.10）。P = 0.013，P <0.001和P分别<0.001，且电子转运链复合物的表达没有显着变化。结论：这些在人体心肌中的发现证实了在啮齿类动物中的研究，在这些啮齿类动物中，收缩功能障碍与FOXO3a-BNIP3途径的活化以及线粒体动力学，生物发生和功能的改变有关。