title: Excess Linoleic Acid Increases Collagen I/III Ratio and "Stiffens" the Heart Muscle Following High Fat Diets.
abstract: Controversy exists on the benefits versus harms of n-6 polyunsaturated fatty acids (n-6 PUFA). Although n-6 PUFA demonstrates anti-atherosclerotic properties, survival following cardiac remodeling may be compromised. We hypothesized that n-6 PUFA like linoleic acid (LA) or other downstream PUFAs like γ-linolenic acid or arachidonic acid alter the transforming growth factor-β (TGFβ)-collagen axis in the heart. Excess dietary LA increased the collagen I/III ratio in the mouse myocardium, leading to cardiac "stiffening" characterized by impaired transmitral flow indicative of early diastolic dysfunction within 5 weeks. In vitro, LA under TGFβ1 stimulation increased collagen I and lysyl oxidase (LOX), the enzyme that cross-links soluble collagen resulting in deposited collagen. Overexpression of fatty acid desaturase 2 (fads2), which metabolizes LA to downstream PUFAs, reduced collagen deposits, LOX maturation, and activity with LA, whereas overexpressing fads1, unrelated to LA desaturation, did not. Furthermore, fads2 knockdown by RNAi elevated LOX activity and collagen deposits in fibroblasts with LA but not oleic acid, implying a buildup of LA for aggravating such pro-fibrotic effects. As direct incubation with γ-linolenic acid or arachidonic acid also attenuated collagen deposits and LOX activity, we concluded that LA itself, independent of other downstream PUFAs, promotes the pro-fibrotic effects of n-6 PUFA. Overall, these results attempt to reconcile opposing views of n-6 PUFA on the cardiovascular system and present evidence supporting a cardiac muscle-specific effect of n-6 PUFAs. Therefore, aggravation of the collagen I/III ratio and cardiac stiffening by excess n-6 PUFA represent a novel pathway of cardiac lipotoxicity caused by high n-6 PUFA diets.
authors.affiliation: From the Department of Biology, IK Barber School of Arts and Sciences, and.
authors.forename: Julianne
authors.initials: J
authors.lastname: Beam
authors.affiliation: From the Department of Biology, IK Barber School of Arts and Sciences, and.
authors.forename: Amy
authors.initials: A
authors.lastname: Botta
authors.affiliation: From the Department of Biology, IK Barber School of Arts and Sciences, and.
authors.forename: Jiayu
authors.initials: J
authors.lastname: Ye
authors.affiliation: Molecular and Cellular Pharmacology Research Group, Faculty of Pharmaceutical Sciences, British Columbia-Okanagan, Kelowna, British Columbia BC V1V 1V7, Canada, and the Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Main Road, Minia 11432, Egypt.
authors.forename: Hesham
authors.initials: H
authors.lastname: Soliman
authors.affiliation: From the Department of Biology, IK Barber School of Arts and Sciences, and.
authors.forename: Brieanne J
authors.initials: BJ
authors.lastname: Matier
authors.affiliation: From the Department of Biology, IK Barber School of Arts and Sciences, and.
authors.forename: Mary
authors.initials: M
authors.lastname: Forrest
authors.affiliation: Molecular and Cellular Pharmacology Research Group, Faculty of Pharmaceutical Sciences, British Columbia-Okanagan, Kelowna, British Columbia BC V1V 1V7, Canada, and.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: MacLeod
authors.affiliation: From the Department of Biology, IK Barber School of Arts and Sciences, and sanjoy.ghosh@ubc.ca.
authors.forename: Sanjoy
authors.initials: S
authors.lastname: Ghosh
mesh_terms: D000818:Animals; D024042:Collagen Type I / Q000378:metabolism*; D024061:Collagen Type III / Q000378:metabolism*; D004042:Dietary Fats, Unsaturated / Q000009:adverse effects* / Q000494:pharmacology; D019787:Linoleic Acid / Q000009:adverse effects* / Q000494:pharmacology; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D024061:Collagen Type III; D004042:Dietary Fats, Unsaturated; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D019787:Linoleic Acid; D013230:Stearoyl-CoA Desaturase; D008249:Protein-Lysine 6-Oxidase
keywords: collagen; fatty acid metabolism; heart failure; lysyl oxidase; polyunsaturated fatty acid (PUFA)