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

Abstract

BackgroundThe 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.MethodsPAH 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.ResultsMCT60 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.ConclusionsOur 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.

Postnatal Hyperoxia Exposure Durably Impairs Right Ventricular Function and Mitochondrial Biogenesis

“…The presence of dysregulated mitochondrial dynamics identified in this study, including impaired mitochondrial biogenesis and mitochondrial DNA damage, may suggest a direct deleterious effect of prematurity and Hx on the RV. Clearly, a direct contribution from the coexisting pulmonary hypertension cannot be completely ruled out, as mitochondrial dysfunction and metabolic gene reprogramming within the RV have previously been identified in animal models and humans with pulmonary arterial hypertension (32)(33)(34). However, these are typically models of RV failure, and mitochondrial dysfunction and impaired biogenesis were not demonstrated in the pulmonary artery banding model of chronic pressure overload (32), which appears more akin, in many ways, to the current postnatal Hx model.…”

Acute detachment of hexokinase II from mitochondria modestly increases oxygen consumption of the intact mouse heart

“…These modest HKII changes probably partly explain why only modest or even no changes in cardiac metabolism were observed. Importantly, these modest changes in HKII mimic the changes in HKII that occur during pathophysiological interventions such as IR and ischemic preconditioning [24 -26], type I and type II diabetes [4], insulin treatment [24,39], or cardiac remodeling during hypertrophy and heart failure [6,40]. Were we to use a complete knockout of HKII or transgenic overexpression of HKII by more than a factor of 5, larger changes in metabolism would probably have occurred.…”

“…HKI is present in almost all cells, mainly localized at the outer mitochondrial membrane, and hardly regulated by hormonal or metabolic signals. In contrast, HKII is mostly present in insulin-sensitive tissue (skeletal muscle, adipose tissue, heart) with its activity, expression and cellular localization (cytosolic or mitochondrial) highly regulated by hormonal or metabolic signals, and responsive to pathological conditions such as diabetes, heart failure, cancer and ischemia-reperfusion (IR) [2][3][4][5][6][7].…”

Novel putative pharmacological therapies to protect the right ventricle in pulmonary hypertension: a review of current literature

“…Aside from its role in the lung, they are equally important in RV remodelling in response to PH (Tang et al, ; Vonk‐Noordegraaf et al, ; Ryan and Archer, ; Ryan et al, ). In PH, the RV displays decreased mitochondrial content, mitochondria with abnormal shape and size, impaired fatty acid oxidation and a glycolytic shift towards glycolysis (Enache et al, ; Gomez‐Arroyo et al, ; Vonk‐Noordegraaf et al, ; Balestra et al, ; Bruns et al, ; Sun et al, ). In PH, cardiomyocytes have a mitochondrial‐metabolic phenotype similar to cancer (Ryan and Archer, ).…”

“…These interventions regressed pulmonary vascular obstruction and improved haemodynamic and RV contractility, increased cardiac output and reduced RV remodelling (Marsboom et al, ; Ryan et al, ). Other possible therapeutic targets could also be mitochondria‐specific drugs that aim to modulate mitochondrial function/efficiency (Enache et al, ; Gomez‐Arroyo et al, ; Balestra et al, ). There is a need for future studies that investigate the full scope of RV‐mitochondrial dysfunction in models of PH.…”