Adaptations in Protein Expression and Regulated Activity of Pyruvate Dehydrogenase Multienzyme Complex in Human Systolic Heart Failure.

Freya L Sheeran,Michael M Cheung,Salvatore Pepe,Norman Y Liaw,Julie Angerosa

doi:10.1155/2019/4532592

Abstract

Pyruvate dehydrogenase (PDH) complex, a multienzyme complex at the nexus of glycolytic and Krebs cycles, provides acetyl-CoA to the Krebs cycle and NADH to complex I thus supporting a critical role in mitochondrial energy production and cellular survival. PDH activity is regulated by pyruvate dehydrogenase phosphatases (PDP1, PDP2), pyruvate dehydrogenase kinases (PDK 1-4), and mitochondrial pyruvate carriers (MPC1, MPC2). As NADH-dependent oxidative phosphorylation is diminished in systolic heart failure, we tested whether the left ventricular myocardium (LV) from end-stage systolic adult heart failure patients (n = 26) exhibits altered expression of PDH complex subunits, PDK, MPC, PDP, and PDH complex activity, compared to LV from nonfailing donor hearts (n = 21). Compared to nonfailing LV, PDH activity and relative expression levels of E2, E3bp, E1α, and E1β subunits were greater in LV failure. PDK4, MPC1, and MPC2 expressions were decreased in failing LV, whereas PDP1, PDP2, PDK1, and PDK2 expressions did not differ between nonfailing and failing LV. In order to examine PDK4 further, donor human LV cardiomyocytes were induced in culture to hypertrophy with 0.1 μM angiotensin II and treated with PDK inhibitors (0.2 mM dichloroacetate, or 5 mM pyruvate) or activators (0.6 mM NADH plus 50 μM acetyl CoA). In isolated hypertrophic cardiomyocytes in vitro, PDK activators and inhibitors increased and decreased PDK4, respectively. In conclusion, in end-stage failing hearts, greater expression of PDH proteins and decreased expression of PDK4, MPC1, and MPC2 were evident with higher rates of PDH activity. These adaptations support sustained capacity for PDH to facilitate glucose metabolism in the face of other failing bioenergetic pathways.

Highlights

Heart failure is a syndrome that involves postmyocardial injury adaptations and remodelling at structural, cellular, humoral, and molecular levels that are evoked to maintain viable cardiac output and systemic circulation
Human pyruvate dehydrogenase (PDH) relies on mitochondrial pyruvate carrier heterodimer protein function (MPC1, MPC2), PDH activity is tightly controlled by phosphorylation of the E1α subunit via PDH kinases (PDK1, PDK2, PDK3, and PDK4) and dephosphorylation by PDH phosphatases (PDP1, PDP2)
PDH activity was significantly increased in the heart failure group when normalized to citrate synthase activity (4 49 ± 0 49 mU/U citrate synthase), representing a 63% increase compared to the nonfailing tissues (2 75 ± 0 51 mU PDH/U citrate synthase, p = 0 023) (Figure 2(a))

Summary

Introduction

Heart failure is a syndrome that involves postmyocardial injury adaptations and remodelling at structural, cellular, humoral, and molecular levels that are evoked to maintain viable cardiac output and systemic circulation. Relative to nonfailing donor LV, we have previously measured decreased activity rates of mitochondrial respiratory enzyme complex I, complex IV, and nicotinamide nucleotide transhydrogenase; the Krebs cycle enzymes isocitrate dehydrogenase, malate dehydrogenase, and aconitase; plus decreased cellular levels of total glutathione and coenzyme Q10, in end-stage failing adult human heart biopsies [4, 5] In these failing myocardial tissues, diminished management of reactive oxygen metabolism augments postoxidative modifications of key mitochondrial proteins and lipids that inhibit enzyme activity [5], cause loss of membrane cardiolipin [6], decrease the activity of the creatine kinase.

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