title: Inhibition of delta-6 desaturase reverses cardiolipin remodeling and prevents contractile dysfunction in the aged mouse heart without altering mitochondrial respiratory function.
abstract: Aging results in a redistribution of polyunsaturated fatty acids (PUFAs) in myocardial phospholipids. In particular, a selective loss of linoleic acid (18:2n6) with reciprocal increases of long-chain PUFAs (eg, arachidonic and docosahexaenoic acids) in the mitochondrial phospholipid cardiolipin correlates with cardiac mitochondrial dysfunction and contractile impairment in aging and related pathologies. In this study, we demonstrate a reversal of this aged-related PUFA redistribution pattern in cardiac mitochondria from aged (25 months) C57Bl/6 mice by inhibition of delta-6 desaturase, the rate limiting enzyme in long-chain PUFA biosynthesis. Interestingly, delta-6 desaturase inhibition had no effect on age-related mitochondrial respiratory dysfunction, H2O2 release, or lipid peroxidation but markedly attenuated cardiac dilatation, hypertrophy, and contractile dysfunction in aged mice. Taken together, our studies indicate that PUFA metabolism strongly influences phospholipid remodeling and cardiac function but dissociates these processes from mitochondrial respiratory dysfunction and oxidant production in the aged mouse heart.
authors.affiliation: Department of Food Science and Human Nutrition.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Mulligan
authors.affiliation: Program in Cell and Molecular Biology.
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Le
authors.affiliation: Department of Biomedical Sciences, and.
authors.forename: Anthony B
authors.initials: AB
authors.lastname: deMooy
authors.affiliation: Program in Cell and Molecular Biology.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Nelson
authors.affiliation: Adam.Chicco@colostate.edu.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Chicco
mesh_terms: D000375:Aging / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002308:Cardiolipins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000378:metabolism; D019787:Linoleic Acid / Q000378:metabolism; D050602:Linoleoyl-CoA Desaturase / Q000037:antagonists & inhibitors*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009206:Myocardium / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology
chemical_list: D002308:Cardiolipins; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D010879:Piperazines; C120986:SC 26196; D019787:Linoleic Acid; D006861:Hydrogen Peroxide; D050602:Linoleoyl-CoA Desaturase
keywords: Cardiolipin; Mitochondria; Oxidative stress.; Phospholipids; Polyunsaturated fatty acids