Increased in vivo mitochondrial oxygenation with right ventricular failure induced by pulmonary arterial hypertension: mitochondrial inhibition as driver of cardiac failure?

Respiratory Research

Coert J Zuurbier²  Willem J van der Laarse³  Patricia AC Specht⁴  Otto Eerbeek¹  Egbert G Mik⁴  Gianmarco M Balestra⁴ 

[1] Department of Anatomy, Embryology and Physiology, AMC, Amsterdam, The Netherlands;Department of Anaesthesiology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105, AZ, The Netherlands;Department of Physiology, VUmc Medical Center, Amsterdam, The Netherlands;Department of Anesthesiology, Laboratory of Experimental Anesthesiology, Erasmus MC- University Medical Center Rotterdam, Rotterdam, The Netherlands

关键词: Pulmonary arterial hypertension;    Heart failure;    Heart hypertrophy;    Mitochondria;    Oxygen;   

Others  :  1135885
DOI  :  10.1186/s12931-015-0178-6

 received in 2014-10-13, accepted in 2015-01-20,  发布年份 2015

【 摘 要 】

Background

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.

Methods

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.

Results

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% FiO_2, 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.

Conclusions

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.

【 授权许可】

   
2015 Balestra et al.; licensee BioMed Central.

【 图 表 】

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