Dataset Information

PDK4 Inhibits Cardiac Pyruvate Oxidation in Late Pregnancy.

ABSTRACT: RATIONALE:Pregnancy profoundly alters maternal physiology. The heart hypertrophies during pregnancy, but its metabolic adaptations, are not well understood. OBJECTIVE:To determine the mechanisms underlying cardiac substrate use during pregnancy. METHODS AND RESULTS:We use here 13C glucose, 13C lactate, and 13C fatty acid tracing analyses to show that hearts in late pregnant mice increase fatty acid uptake and oxidation into the tricarboxylic acid cycle, while reducing glucose and lactate oxidation. Mitochondrial quantity, morphology, and function do not seem altered. Insulin signaling seems intact, and the abundance and localization of the major fatty acid and glucose transporters, CD36 (cluster of differentiation 36) and GLUT4 (glucose transporter type 4), are also unchanged. Rather, we find that the pregnancy hormone progesterone induces PDK4 (pyruvate dehydrogenase kinase 4) in cardiomyocytes and that elevated PDK4 levels in late pregnancy lead to inhibition of PDH (pyruvate dehydrogenase) and pyruvate flux into the tricarboxylic acid cycle. Blocking PDK4 reverses the metabolic changes seen in hearts in late pregnancy. CONCLUSIONS:Taken together, these data indicate that the hormonal environment of late pregnancy promotes metabolic remodeling in the heart at the level of PDH, rather than at the level of insulin signaling.

SUBMITTER: Liu LX

PROVIDER: S-EPMC5722682 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

PDK4 Inhibits Cardiac Pyruvate Oxidation in Late Pregnancy.

Liu Laura X LX Rowe Glenn C GC Yang Steven S Li Jian J Damilano Federico F Chan Mun Chun MC Lu Wenyun W Jang Cholsoon C Wada Shogo S Morley Michael M Hesse Michael M Fleischmann Bernd K BK Rabinowitz Joshua D JD Das Saumya S Rosenzweig Anthony A Arany Zoltan Z

Circulation research 20170919 12

<h4>Rationale</h4>Pregnancy profoundly alters maternal physiology. The heart hypertrophies during pregnancy, but its metabolic adaptations, are not well understood.<h4>Objective</h4>To determine the mechanisms underlying cardiac substrate use during pregnancy.<h4>Methods and results</h4>We use here <sup>13</sup>C glucose, <sup>13</sup>C lactate, and <sup>13</sup>C fatty acid tracing analyses to show that hearts in late pregnant mice increase fatty acid uptake and oxidation into the tricarboxylic ...[more]

PMID: 28928113

Similar Datasets

Project description:Pyruvate dehydrogenase kinase (PDK) is activated in right ventricular hypertrophy (RVH), causing an increase in glycolysis relative to glucose oxidation that impairs right ventricular function. The stimulus for PDK upregulation, its isoform specificity, and the long-term effects of PDK inhibition are unknown. We hypothesize that FOXO1-mediated PDK4 upregulation causes bioenergetic impairment and RV dysfunction, which can be reversed by dichloroacetate. Adult male Fawn-Hooded rats (FHR) with pulmonary arterial hypertension (PAH) and right ventricular hypertrophy (RVH; age 6-12 months) were compared to age-matched controls. Glucose oxidation (GO) and fatty acid oxidation (FAO) were measured at baseline and after acute dichloroacetate (1 mM × 40 min) in isolated working hearts and in freshly dispersed RV myocytes. The effects of chronic dichloroacetate (0.75 g/L drinking water for 6 months) on cardiac output (CO) and exercise capacity were measured in vivo. Expression of PDK4 and its regulatory transcription factor, FOXO1, were also measured in FHR and RV specimens from PAH patients (n = 10). Microarray analysis of 168 genes related to glucose or FA metabolism showed >4-fold upregulation of PDK4, aldolase B, and acyl-coenzyme A oxidase. FOXO1 was increased in FHR RV, whereas HIF-1 ? was unaltered. PDK4 expression was increased, and the inactivated form of FOXO1 decreased in human PAH RV (P < 0.01). Pyruvate dehydrogenase (PDH) inhibition in RVH increased proton production and reduced GO's contribution to the tricarboxylic acid (TCA) cycle. Acutely, dichloroacetate reduced RV proton production and increased GO's contribution (relative to FAO) to the TCA cycle and ATP production in FHR (P < 0.01). Chronically dichloroacetate decreased PDK4 and FOXO1, thereby activating PDH and increasing GO in FHR. These metabolic changes increased CO (84 ± 14 vs. 69 ± 14 ml/min, P < 0.05) and treadmill-walking distance (239 ± 20 vs. 171 ± 22 m, P < 0.05). Chronic dichloroacetate inhibits FOXO1-induced PDK4 upregulation and restores GO, leading to improved bioenergetics and RV function in RVH.

Dataset Information

PDK4 Inhibits Cardiac Pyruvate Oxidation in Late Pregnancy.

Publications

PDK4 Inhibits Cardiac Pyruvate Oxidation in Late Pregnancy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets