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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

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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.

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Acknowledgement

Dr. Archer is supported by The Harold Hines Jr. Chair in Department of Medicine in University of Chicago and NIH-RO1-HL071115. We appreciate the assistance of Dr. William Green and his PhD student Ning Zheng in the immunoblotting studies and Judy U. Earley in the preparation of H&E staining.

Disclosures

The authors have no conflicts to disclose.

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Authors and Affiliations

  1. Section of Cardiology, Department of Medicine, University of Chicago, 5841 South Maryland Avenue (MC6080), Chicago, IL, 60637, USA

    Lin Piao, Yong-Hu Fang, Christian Wietholt, Dalia Urboniene, Peter T. Toth, Glenn Marsboom, Hannah J. Zhang, Idith Haber, Jalees Rehman & Stephen L. Archer

  2. Department of Pediatrics and Cardiovascular Research Group, University of Alberta, Edmonton, Canada

    Virgilio J. J. Cadete & Gary D. Lopaschuk

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  1. Lin Piao
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Correspondence to Stephen L. Archer.

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Piao, L., Fang, YH., Cadete, V.J.J. et al. 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, 47–60 (2010). https://doi.org/10.1007/s00109-009-0524-6

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