Journal of Molecular Medicine

, Volume 88, Issue 1, pp 47–60 | Cite as

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

  • Lin Piao
  • Yong-Hu Fang
  • Virgilio J. J. Cadete
  • Christian Wietholt
  • Dalia Urboniene
  • Peter T. Toth
  • Glenn Marsboom
  • Hannah J. Zhang
  • Idith Haber
  • Jalees Rehman
  • Gary D. Lopaschuk
  • Stephen L. Archer
Original Article

Abstract

Right ventricular hypertrophy (RVH) and RV failure contribute to morbidity and mortality in pulmonary arterial hypertension (PAH). The cause of RV dysfunction and the feasibility of therapeutically targeting the RV are uncertain. We hypothesized that RV dysfunction and electrical remodeling in RVH result, in part, from a glycolytic shift in the myocyte, caused by activation of pyruvate dehydrogenase kinase (PDK). We studied two complementary rat models: RVH + PAH (induced by monocrotaline) and RVH + without PAH (induced by pulmonary artery banding (PAB)). Monocrotaline RVH reduced RV O2-consumption and enhanced glycolysis. RV 2-fluoro-2-deoxy-glucose uptake, Glut-1 expression, and pyruvate dehydrogenase phosphorylation increased in monocrotaline RVH. The RV monophasic action potential duration and QTc interval were prolonged due to decreased expression of repolarizing voltage-gated K+ channels (Kv1.5, Kv4.2). In the RV working heart model, the PDK inhibitor, dichloroacetate, acutely increased glucose oxidation and cardiac work in monocrotaline RVH. Chronic dichloroacetate therapy improved RV repolarization and RV function in vivo and in the RV Langendorff model. In PAB-induced RVH, a similar reduction in cardiac output and glycolytic shift occurred and it too improved with dichloroacetate. In PAB-RVH, the benefit of dichloroacetate on cardiac output was approximately 1/3 that in monocrotaline RVH. The larger effects in monocrotaline RVH likely reflect dichloroacetate’s dual metabolic benefits in that model: regression of vascular disease and direct effects on the RV. Reduction in RV function and electrical remodeling in two models of RVH relevant to human disease (PAH and pulmonic stenosis) result, in part, from a PDK-mediated glycolytic shift in the RV. PDK inhibition partially restores RV function and regresses RVH by restoring RV repolarization and enhancing glucose oxidation. Recognition that a PDK-mediated metabolic shift contributes to contractile and ionic dysfunction in RVH offers insight into the pathophysiology and treatment of RVH.

Keywords

Pulmonary artery banding Pulmonic stenosis Voltage-gated potassium channels (Kv) Warburg hypothesis Mitochondrial metabolism 

Supplementary material

109_2009_524_MOESM1_ESM.pdf (617 kb)
Supplementary 1(PDF 616 kb)

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Lin Piao
    • 1
  • Yong-Hu Fang
    • 1
  • Virgilio J. J. Cadete
    • 2
  • Christian Wietholt
    • 1
  • Dalia Urboniene
    • 1
  • Peter T. Toth
    • 1
  • Glenn Marsboom
    • 1
  • Hannah J. Zhang
    • 1
  • Idith Haber
    • 1
  • Jalees Rehman
    • 1
  • Gary D. Lopaschuk
    • 2
  • Stephen L. Archer
    • 1
  1. 1.Section of Cardiology, Department of MedicineUniversity of ChicagoChicagoUSA
  2. 2.Department of Pediatrics and Cardiovascular Research GroupUniversity of AlbertaEdmontonCanada

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