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

• Published in: Journal of molecular medicine (Berlin, Germany) Germany), 2010-01, Vol.88 (1), p.47-60
• Main Authors: Piao, Lin, Fang, Yong-Hu, Cadete, Virgilio J. J., Wietholt, Christian, Urboniene, Dalia, Toth, Peter T., Marsboom, Glenn, Zhang, Hannah J., Haber, Idith, Rehman, Jalees, Lopaschuk, Gary D., Archer, Stephen L.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; General aspects; Heart Ventricles - pathology; Heart Ventricles - physiopathology; Hemodynamics; Human Genetics; Humans; Hypertrophy, Right Ventricular - enzymology; Hypertrophy, Right Ventricular - pathology; Hypertrophy, Right Ventricular - physiopathology; Hypertrophy, Right Ventricular - therapy; Internal Medicine; Male; Medical sciences; Molecular Medicine; Original Article; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Rats; Rats, Sprague-Dawley
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-009-0524-6

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 O 2 -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 QT c 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.