title: Delta-6-desaturase links polyunsaturated fatty acid metabolism with phospholipid remodeling and disease progression in heart failure.
abstract: 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.
  
  
  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 [corrected].
authors.affiliation: Integrative Cardiac Biology Laboratory.
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Le
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Mulligan
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Routh
authors.forename: Gerrit J
authors.initials: GJ
authors.lastname: Bouma
authors.forename: Melinda A
authors.initials: MA
authors.lastname: Frye
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Jeckel
authors.forename: Genevieve C
authors.initials: GC
authors.lastname: Sparagna
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Lynch
authors.forename: Russell L
authors.initials: RL
authors.lastname: Moore
authors.forename: Sylvia A
authors.initials: SA
authors.lastname: McCune
authors.forename: Michael
authors.initials: M
authors.lastname: Bristow
authors.forename: Simona
authors.initials: S
authors.lastname: Zarini
authors.forename: Robert C
authors.initials: RC
authors.lastname: Murphy
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Chicco
mesh_terms: D000818:Animals; D020169:Caspases / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D006439:Hemodynamics / Q000502:physiology; D006801:Humans; D050602:Linoleoyl-CoA Desaturase / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D010743:Phospholipids; D050602:Linoleoyl-CoA Desaturase; D020169:Caspases
keywords: fatty acid synthases; heart failure; hypertension; inflammation; metabolism