The Role of Nonglycolytic Glucose Metabolism in Myocardial Recovery Upon Mechanical Unloading and Circulatory Support in Chronic Heart Failure
| Autor: | Thirupura S. Shankar, Stephen H. McKellar, Craig H. Selzman, Dipayan Chaudhuri, Aspasia Thodou Krokidi, James C. Fang, Abdallah G. Kfoury, Iosif Taleb, Dinesh K. A. Ramadurai, E. Dale Abel, Peter Ferrin, Omar Wever-Pinzon, Rachit Badolia, Jared Rutter, Sutip Navankasattusas, Michael Yin, Stavros G. Drakos |
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| Rok vydání: | 2020 |
| Předmět: |
medicine.medical_specialty
One-carbon metabolism Heart Ventricles Comorbidity 030204 cardiovascular system & hematology Carbohydrate metabolism Pentose phosphate pathway Article 03 medical and health sciences 0302 clinical medicine Physiology (medical) Internal medicine medicine Humans Metabolomics Reverse remodeling 030304 developmental biology Heart Failure 0303 health sciences business.industry Myocardium Stroke Volume medicine.disease Structure and function Glucose Heart failure Circulatory system Cardiology Metabolome Heart-Assist Devices Cardiology and Cardiovascular Medicine business Energy Metabolism Glycolysis Oxidation-Reduction Metabolic Networks and Pathways |
| Zdroj: | Circulation |
| ISSN: | 1524-4539 |
| Popis: | Background: Significant improvements in myocardial structure and function have been reported in some patients with advanced heart failure (termed responders [R]) following left ventricular assist device (LVAD)–induced mechanical unloading. This therapeutic strategy may alter myocardial energy metabolism in a manner that reverses the deleterious metabolic adaptations of the failing heart. Specifically, our previous work demonstrated a post-LVAD dissociation of glycolysis and oxidative-phosphorylation characterized by induction of glycolysis without subsequent increase in pyruvate oxidation through the tricarboxylic acid cycle. The underlying mechanisms responsible for this dissociation are not well understood. We hypothesized that the accumulated glycolytic intermediates are channeled into cardioprotective and repair pathways, such as the pentose-phosphate pathway and 1-carbon metabolism, which may mediate myocardial recovery in R. Methods: We prospectively obtained paired left ventricular apical myocardial tissue from nonfailing donor hearts as well as R and nonresponders at LVAD implantation (pre-LVAD) and transplantation (post-LVAD). We conducted protein expression and metabolite profiling and evaluated mitochondrial structure using electron microscopy. Results: Western blot analysis shows significant increase in rate-limiting enzymes of pentose-phosphate pathway and 1-carbon metabolism in post-LVAD R (post-R) as compared with post-LVAD nonresponders (post-NR). The metabolite levels of these enzyme substrates, such as sedoheptulose-6-phosphate (pentose phosphate pathway) and serine and glycine (1-carbon metabolism) were also decreased in Post-R. Furthermore, post-R had significantly higher reduced nicotinamide adenine dinucleotide phosphate levels, reduced reactive oxygen species levels, improved mitochondrial density, and enhanced glycosylation of the extracellular matrix protein, α-dystroglycan, all consistent with enhanced pentose-phosphate pathway and 1-carbon metabolism that correlated with the observed myocardial recovery. Conclusions: The recovering heart appears to direct glycolytic metabolites into pentose-phosphate pathway and 1-carbon metabolism, which could contribute to cardioprotection by generating reduced nicotinamide adenine dinucleotide phosphate to enhance biosynthesis and by reducing oxidative stress. These findings provide further insights into mechanisms responsible for the beneficial effect of glycolysis induction during the recovery of failing human hearts after mechanical unloading. |
| Databáze: | OpenAIRE |
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