Format

Send to

Choose Destination
Respir Res. 2015 Feb 3;16:6. doi: 10.1186/s12931-015-0178-6.

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

Author information

1
Department of Anesthesiology, Laboratory of Experimental Anesthesiology, Erasmus MC- University Medical Center Rotterdam, Rotterdam, The Netherlands. gianmarco.Balestra@usb.ch.
2
Department of Anesthesiology, Laboratory of Experimental Anesthesiology, Erasmus MC- University Medical Center Rotterdam, Rotterdam, The Netherlands. e.mik@erasmusmc.nl.
3
Department of Anatomy, Embryology and Physiology, AMC, Amsterdam, The Netherlands. o.eerbeek@amc.uva.nl.
4
Department of Anesthesiology, Laboratory of Experimental Anesthesiology, Erasmus MC- University Medical Center Rotterdam, Rotterdam, The Netherlands. p.specht@erasmusmc.nl.
5
Department of Physiology, VUmc Medical Center, Amsterdam, The Netherlands. wj.vanderlaarse@vumc.nl.
6
Department of Anesthesiology, Laboratory of Experimental Intensive Care and Anesthesiology, AMC, Amsterdam, The Netherlands. c.j.zuurbier@amc.uva.nl.
7
Department of Anaesthesiology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105, AZ, Amsterdam, The Netherlands. c.j.zuurbier@amc.uva.nl.

Abstract

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% 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.

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.

PMID:
25645252
PMCID:
PMC4320611
DOI:
10.1186/s12931-015-0178-6
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center