Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
Chin Med J (Engl). 2012 Mar;125(5):807-14.
Mitochondrial dysfunction plays a pivotal role in the progression of left ventricular (LV) remodeling and heart failure (HF). Recombinant human neuregulin-1 (rhNRG-1) improves cardiac function in models of experimental HF and in clinical trials; however, its impact on mitochondrial function during chronic HF remains largely unknown. The purpose of this study was to investigate whether rhNRG-1 could attenuate the functional and structural changes that occur in cardiac mitochondria in a rat model of HF induced by myocardial infarction.
Sixty adult rats underwent sham or coronary ligation to induce HF. Four weeks after ligation, 29 animals with LV ejective fraction ≤ 50% were randomized to receive either vehicle or rhNRG-1 (10 µg×kg(-1)×d(-1), I.V.) for 10 days, another 12 sham-operated animals were given no treatment. Echocardiography was used to determine physiological changes. Mitochondrial membrane potential (MMP), respiratory function and tissue adenosine triphosphate (ATP) production were analyzed. Cytochrome c expression and cardiomyocyte apoptosis were determined. Oxidative stress was evaluated by reactive oxygen species production using fluorescence assays and gene expression of glutathione peroxidase measured by real-time quantitative PCR.
Compared with sham-operated animals, vehicle treated HF rats exhibited severe LV remodeling and dysfunction, significant mitochondrial dysfunction, increased mitochondrial cytochrome c release, increased myocyte apoptosis and enhanced oxidative stress. Short-term treatment with rhNRG-1 significantly attenuated LV remodeling and cardiac function. Concomitant with this change, mitochondrial dysfunction was significantly attenuated; with ATP production, MMP and respiratory function restored, cytochrome c release and apoptosis inhibited, and oxidative stress reduced.
The present study demonstrated that rhNRG-1 can significantly improve LV remodeling and cardiac function in the failing heart, this beneficial effect is related to reducing mitochondrial dysfunction, myocyte apoptosis and oxidative stress.
线粒体功能障碍在左心室（LV）重构和心力衰竭（HF）的进展中起着关键作用。重组人神经调节蛋白-1（rhNRG-1）可改善实验性 HF 模型和临床试验中心脏功能；然而，其在慢性 HF 期间对线粒体功能的影响在很大程度上尚不清楚。本研究旨在探讨 rhNRG-1 是否可以减轻心肌梗死后 HF 大鼠模型中心脏线粒体发生的功能和结构变化。
60 只成年大鼠接受假手术或冠状动脉结扎以诱导 HF。结扎后 4 周，29 只左心室射血分数≤50%的动物随机接受载体或 rhNRG-1（10µg×kg-1×d-1，静脉内）治疗 10 天，另外 12 只假手术动物不给予任何治疗。超声心动图用于确定生理变化。分析线粒体膜电位（MMP）、呼吸功能和组织三磷酸腺苷（ATP）产生。测定细胞色素 c 表达和心肌细胞凋亡。通过荧光测定法评估活性氧物质（ROS）的产生来评估氧化应激，并通过实时定量 PCR 测量谷胱甘肽过氧化物酶的基因表达。
与假手术动物相比，载体治疗的 HF 大鼠表现出严重的 LV 重构和功能障碍、显著的线粒体功能障碍、增加的线粒体细胞色素 c 释放、增加的心肌细胞凋亡和增强的氧化应激。rhNRG-1 短期治疗可显著减轻 LV 重构和心脏功能。与此变化伴随的是，线粒体功能显著改善；伴随着 ATP 产生、MMP 和呼吸功能的恢复，细胞色素 c 释放和凋亡受到抑制，氧化应激减少。
本研究表明，rhNRG-1 可显著改善衰竭心脏的 LV 重构和心脏功能，这种有益作用与减轻线粒体功能障碍、心肌细胞凋亡和氧化应激有关。
