title: A metabolic remodeling in right ventricular hypertrophy is associated with decreased angiogenesis and a transition from a compensated to a decompensated state in pulmonary hypertension.
abstract: Right ventricular (RV) failure is an important clinical problem with no available therapies, largely because its molecular mechanisms are unknown. Mitochondrial remodeling resulting to a metabolic shift toward glycolysis has been described in RV hypertrophy (RVH), but it is unknown whether this is beneficial or detrimental. While clinically RV failure follows a period of compensation, the transition from a compensated (cRVH) to a decompensated hypertrophied RV (dRVH) is not studied in animal models. We modeled the natural history of RVH and failure in the monocrotaline rat model of pulmonary hypertension by serially assessing clinically relevant parameters in the same animal. We defined dRVH as the stage in which RV systolic pressure started decreasing, along with the cardiac output, while the RV continued to remodel. dRVH was characterized by ascites, weight loss, and high mortality, compared to cRVH. A cRVH myocardium had hyperpolarized mitochondria and low production of mitochondria-derived reactive oxygen species (mROS), activated hypoxia-inducible factor 1α (HIF1α), and increased levels of glucose transporter 1, vascular endothelial growth factor, and stromal-derived factor 1, promoting increased glucose uptake (measured by positron emission tomography-computed tomography) and angiogenesis measured by lectin imaging in vivo. The transition to dRVH was marked by a sharp rise in mROS, inhibition of HIF1α, and activation of p53, both of which contributed to down-regulation of pyruvate dehydrogenase kinase and decreased glucose uptake. This transition was also associated with a sharp decrease in angiogenic factors and angiogenesis. We show that the previously described metabolic shift, promoting HIF1α activation and angiogenesis, is not sustained during the progression of RV failure. The loss of this beneficial remodeling may be triggered by a rise in mROS resulting in HIF1α inhibition and suppressed angiogenesis. The resultant ischemia may contribute to the rapid deterioration of RV function upon entrance to a decompensation phase. The use of clinical criteria and techniques to define and study dRVH facilitates clinical translation of our findings with direct implications for RV therapeutic and biomarker discovery programs.
  
  
  CONCLUSIONS
  Decreased RV angiogenesis marks the transition from a cRVH to a dRVH. The RVs in cRVH animals are associated with decreased mROS and increased HIF1α activity compared to dRVH. The RVs in cRVH animals have increased GLUT1 levels and increased glucose uptake compared to the dRVH.
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Alberta, Canada, T6G 2B7.
authors.forename: Gopinath
authors.initials: G
authors.lastname: Sutendra
authors.forename: Peter
authors.initials: P
authors.lastname: Dromparis
authors.forename: Roxane
authors.initials: R
authors.lastname: Paulin
authors.forename: Sotirios
authors.initials: S
authors.lastname: Zervopoulos
authors.forename: Alois
authors.initials: A
authors.lastname: Haromy
authors.forename: Jayan
authors.initials: J
authors.lastname: Nagendran
authors.forename: Evangelos D
authors.initials: ED
authors.lastname: Michelakis
mesh_terms: D000818:Animals; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology*; D006976:Hypertension, Pulmonary / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000150:complications* / Q000378:metabolism* / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D051272:Glucose Transporter Type 1; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; C495679:Slc2a1 protein, rat; D005947:Glucose