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
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.
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.
KeywordsHypoxia-inducible factor 1α Angiogenesis Metabolism Right ventricular failure Ischemia
- 7.van de Veerdonk MC, Kind T, Marcus JT, Mauritz GJ, Heymans MW, Bogaard HJ, Boonstra A, Marques KM, Westerhof N, Vonk-Noordegraaf A (2011) Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy. J Am Coll Cardiol 58:2511–2519PubMedCrossRefGoogle Scholar
- 10.Piao L, Fang YH, Cadete VJ, Wietholt C, Urboniene D, Toth PT, Marsboom G, Zhang HJ, Haber I, Rehman J et al (2010) The inhibition of pyruvate dehydrogenase kinase improves impaired cardiac function and electrical remodeling in two models of right ventricular hypertrophy: resuscitating the hibernating right ventricle. J Mol Med 88:47–60PubMedCrossRefGoogle Scholar
- 20.Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Harry G et al (2007) A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11:37–51PubMedCrossRefGoogle Scholar
- 23.Oikawa M, Kagaya Y, Otani H, Sakuma M, Demachi J, Suzuki J, Takahashi T, Nawata J, Ido T, Watanabe J et al (2005) Increased [18F]fluorodeoxyglucose accumulation in right ventricular free wall in patients with pulmonary hypertension and the effect of epoprostenol. J Am Coll Cardiol 45:1849–1855PubMedCrossRefGoogle Scholar
- 40.Gomez-Arroyo J, Mizuno S, Szczepanek K, Van Tassell B, Natarajan R, dos Remedios CG, Drake JI, Farkas L, Kraskauskas D, Wijesinghe DS et al (2012) Metabolic gene remodeling and mitochondrial dysfunction in failing right ventricular hypertrophy secondary to pulmonary arterial hypertension. Circ Heart Fail 6:136–144PubMedCrossRefGoogle Scholar
- 41.Lundgrin EL, Park MM, Sharp J, Tang WH, Thomas JD, Asosingh K, Comhair SA, Difilippo FP, Neumann DR, Davis L et al (2013) Fasting 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography to detect metabolic changes in pulmonary arterial hypertension hearts over 1 year. Ann Am Thorac Soc 10:1–9PubMedGoogle Scholar