Induction of mitochondrial nitrative damage and cardiac dysfunction by chronic provision of dietary omega-6 polyunsaturated fatty acids.
Increased awareness of obesity has led to a dietary shift toward "heart-friendly" vegetable oils containing omega-6 polyunsaturated fatty acid (omega-6 PUFA). In addition to its beneficial effects, omega-6 PUFA also exhibits proinflammatory and prooxidative properties. We hypothesized that chronic dietary omega-6 PUFA can induce free radical generation, predisposing the cardiac mitochondria to oxidative damage. Male Wistar rats were fed a diet supplemented with 20% w/w sunflower oil, rich in omega-6 PUFA (HP) or normal laboratory chow (LP) for 4 weeks. HP feeding augmented phospholipase A(2) activity and breakdown of cardiolipin, a mitochondrial phospholipid. HP hearts also demonstrated elevated inducible nitric oxide synthase expression, loss of Mn superoxide dismutase, and increased mitochondrial nitrotyrosine levels. In these hearts, oxidative damage to mitochondrial DNA (mDNA) was demonstrated by 8-hydroxyguanosine immunopositivity, overexpression of DNA repair enzymes, and a decrease in the mRNA expression of specific respiratory subunits encoded by the mDNA. Functionally, at higher workloads, HP hearts also demonstrated a greater decline in cardiac work than LP, suggesting a compromised mitochondrial reserve. Our study, for the first time, demonstrates that consumption of a high fat diet rich in omega-6 PUFA for only 4 weeks instigates mitochondrial nitrosative damage and causes cardiac dysfunction at high afterloads.
Ghosh
Sanjoy
S
Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
Kewalramani
Girish
G
Yuen
Gloria
G
Pulinilkunnil
Thomas
T
An
Ding
D
Innis
Sheila M
SM
Allard
Michael F
MF
Wambolt
Richard B
RB
Qi
Dake
D
Abrahani
Ashraf
A
Rodrigues
Brian
B
D000818:Animals; D015153:Blotting, Western; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D004032:Diet; D043371:Fatty Acids, Omega-6 / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000187:drug effects; D006331:Heart Diseases / Q000209:etiology* / Q000378:metabolism; D008054:Lipid Peroxides / Q000378:metabolism; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress; D010741:Phospholipases A / Q000378:metabolism; D010938:Plant Oils / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D000074242:Sunflower Oil; D013482:Superoxide Dismutase / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D004272:DNA, Mitochondrial; D043371:Fatty Acids, Omega-6; D008054:Lipid Peroxides; D010938:Plant Oils; D000074242:Sunflower Oil; C002744:3-nitrotyrosine; D014443:Tyrosine; D052247:Nitric Oxide Synthase Type II; D013482:Superoxide Dismutase; D010741:Phospholipases A