Balestra Gianmarco M, Mik Egbert G, Eerbeek Otto, Specht Patricia A C, van der Laarse Willem J, Zuurbier Coert J
Department of Anesthesiology, Laboratory of Experimental Anesthesiology, Erasmus MC- University Medical Center Rotterdam, Rotterdam, The Netherlands.
Department of Anatomy, Embryology and Physiology, AMC, Amsterdam, The Netherlands.
Respir Res. 2015 Feb 3;16(1):6. doi: 10.1186/s12931-015-0178-6.
The leading cause of mortality due to pulmonary arterial hypertension (PAH) is failure of the cardiac right ventricle. It has long been hypothesized that during the development of chronic cardiac failure the heart becomes energy deprived, possibly due to shortage of oxygen at the level of cardiomyocyte mitochondria. However, direct evaluation of oxygen tension levels within the in vivo right ventricle during PAH is currently lacking. Here we directly evaluated this hypothesis by using a recently reported technique of oxygen-dependent quenching of delayed fluorescence of mitochondrial protoprophyrin IX, to determine the distribution of mitochondrial oxygen tension (mitoPO2) within the right ventricle (RV) subjected to progressive PAH.
PAH was induced through a single injection of monocrotaline (MCT). Control (saline-injected), compensated RV hypertrophy (30 mg/kg MCT; MCT30), and RV failure (60 mg/kg MCT; MCT60) rats were compared 4 wk after treatment. The distribution of mitoPO2 within the RV was determined in mechanically-ventilated, anaesthetized animals, applying different inspired oxygen (FiO2) levels and two increment dosages of dobutamine.
MCT60 resulted in RV failure (increased mortality, weight loss, increased lung weight), MCT30 resulted in compensated RV hypertrophy. At 30% or 40% FiO2, necessary to obtain physiological arterial PO2 in the diseased animals, RV failure rats had significantly less mitochondria (15% of total mitochondria) in the 0-20 mmHg mitoPO2 range than hypertrophied RV rats (48%) or control rats (54%). Only when oxygen supply was reduced to 21% FiO2, resulting in low arterial PO2 for the MCT60 animals, or when oxygen demand increased with high dose dobutamine, the number of failing RV mitochondria with low oxygen became similar to control RV. In addition, metabolic enzyme analysis revealed similar mitochondrial mass, increased glycolytic hexokinase activity following MCT, with increased lactate dehydrogenase activity only in compensated hypertrophied RV.
Our novel observation of increased mitochondrial oxygenation suggests down-regulation of in vivo mitochondrial oxygen consumption, in the absence of hypoxia, with transition towards right ventricular failure induced by pulmonary arterial hypertension.
肺动脉高压（PAH）导致死亡的主要原因是右心室衰竭。长期以来，人们一直推测，在慢性心力衰竭发展过程中，心脏可能因心肌细胞线粒体水平的氧气短缺而出现能量供应不足。然而，目前缺乏对PAH期间体内右心室内氧张力水平的直接评估。在此，我们通过使用最近报道的一种依赖氧气淬灭线粒体原卟啉IX延迟荧光的技术，直接评估这一假设，以确定在进行性PAH的右心室（RV）内线粒体氧张力（mitoPO2）的分布。
通过单次注射野百合碱（MCT）诱导PAH。在治疗4周后，比较对照组（注射生理盐水）、代偿性右心室肥厚组（30mg/kg MCT；MCT30）和右心室衰竭组（60mg/kg MCT；MCT60）大鼠。在机械通气、麻醉的动物中，应用不同的吸入氧（FiO2）水平和两种递增剂量的多巴酚丁胺，测定右心室内mitoPO2的分布。
MCT60导致右心室衰竭（死亡率增加、体重减轻、肺重量增加），MCT30导致代偿性右心室肥厚。在患病动物中，为获得生理动脉血氧分压所需的30%或40% FiO2条件下，右心室衰竭大鼠在0 - 20 mmHg mitoPO2范围内的线粒体显著少于肥厚性右心室大鼠（48%）或对照大鼠（54%）。只有当氧气供应降至21% FiO2，导致MCT60动物的动脉血氧分压较低时，或者当高剂量多巴酚丁胺增加氧气需求时，低氧的衰竭右心室线粒体数量才与对照右心室相似。此外，代谢酶分析显示线粒体质量相似，MCT后糖酵解己糖激酶活性增加，仅在代偿性肥厚的右心室中乳酸脱氢酶活性增加。
我们对线粒体氧合增加的新观察表明，在无缺氧情况下，随着肺动脉高压诱导的右心室衰竭的转变，体内线粒体氧消耗下调。
