Delta-6-desaturase Links Polyunsaturated Fatty Acid Metabolism With Phospholipid Remodeling and Disease Progression in Heart Failure
| Autor: | Catherine H. Le, Robert C. Murphy, Christopher M. Mulligan, Gerrit J. Bouma, Melissa A. Routh, Michael R. Bristow, Russell L. Moore, Genevieve C. Sparagna, Kimberly M. Jeckel, Sylvia A. McCune, Simona Zarini, Adam J. Chicco, Melinda A. Frye, Joshua M. Lynch |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Fatty Acid Synthases medicine.medical_specialty Linoleic acid Phospholipid Linoleoyl-CoA Desaturase chemistry.chemical_compound Rats Inbred SHR Internal medicine medicine Animals Humans Enzyme Inhibitors Phospholipids Heart Failure Pressure overload chemistry.chemical_classification business.industry Myocardium Hemodynamics Fatty acid Delta-6-desaturase Rats Disease Models Animal Endocrinology chemistry Docosahexaenoic acid Caspases Disease Progression Fatty Acids Unsaturated Cytokines Cardiology and Cardiovascular Medicine business Polyunsaturated fatty acid |
| Zdroj: | Circulation: Heart Failure. 7:172-183 |
| ISSN: | 1941-3297 1941-3289 |
| Popis: | Background— Remodeling of myocardial phospholipids has been reported in various forms of heart failure for decades, but the mechanism and pathophysiological relevance of this phenomenon have remained unclear. We examined the hypothesis that δ-6 desaturase (D6D), the rate-limiting enzyme in long-chain polyunsaturated fatty acid biosynthesis, mediates the signature pattern of fatty acid redistribution observed in myocardial phospholipids after chronic pressure overload and explored plausible links between this process and disease pathogenesis. Methods and Results— Compositional analysis of phospholipids from hearts explanted from patients with dilated cardiomyopathy revealed elevated polyunsaturated fatty acid product/precursor ratios reflective of D6D hyperactivity, manifesting primarily as lower levels of linoleic acid with reciprocally higher levels of arachidonic and docosahexaenoic acids. This pattern of remodeling was attenuated in failing hearts chronically unloaded with a left ventricular assist device. Chronic inhibition of D6D in vivo reversed similar patterns of myocardial polyunsaturated fatty acid redistribution in rat models of pressure overload and hypertensive heart disease and significantly attenuated cardiac hypertrophy, fibrosis, and contractile dysfunction in both models. D6D inhibition also attenuated myocardial elevations in pathogenic eicosanoid species, lipid peroxidation, and extracellular receptor kinase 1/2 activation; normalized cardiolipin composition in mitochondria; reduced circulating levels of inflammatory cytokines; and elicited model-specific effects on cardiac mitochondrial respiratory efficiency, nuclear factor κ B activation, and caspase activities. Conclusions— These studies demonstrate a pivotal role of essential fatty acid metabolism in myocardial phospholipid remodeling induced by hemodynamic stress and reveal novel links between this phenomenon and the propagation of multiple pathogenic systems involved in maladaptive cardiac remodeling and contractile dysfunction. |
| Databáze: | OpenAIRE |
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