Evidence of mitochondrial nitrosative damage and energy stress behind omega‐6 PUFA induced cardiac dysfunction

Abstract

Heightened awareness of obesity and its complications has led to an indiscriminate substitution of atherogenic saturated cooking fats with “heart-friendly” refined vegetable oils like sunflower oil, rich in ω-6 polyunsaturated fatty acids (PUFA) in the Western diet. Interestingly, recent studies have suggested ω-6 PUFA to be pro-inflammatory for the coronary vasculature. However, its effects on the heart muscle itself remain obscure. Thus, we examined the in vivo signaling in Wistar rat hearts following a low ω-6 PUFA (10% of energy, LP) or high ω-6 PUFA (40% of energy, HP) diet for 4 weeks. HP feeding increased phospholipase A2 and breakdown of phospholipids like mitochondrial cardiolipin crucial for ATP production. HP hearts also demonstrated increased inducible nitric oxide synthase expression and loss of Mn superoxide dismutase, a mitochondrial antioxidant. This was followed by an increase in nitrotyrosine, a biomarker for peroxynitrite radical. As peroxynitrite oxidatively damages mitochondrial DNA (mDNA), immunohistochemistry of 8-oxo-7,8-dihydroguanosine, an oxidized DNA byproduct, revealed extensive mDNA damage in HP hearts. This was accompanied with decreased gene expression of ND1 and ATPase 6, respiratory subunits encoded by the mDNA. Such a loss of respiratory subunits along with cardiolipin loss could precipitate cardiac energy deficit. As a functional confirmation, HP hearts failed specifically at elevated afterloads (135mm Hg) indicating a lack of energy reserve that was supported by an increase in phosphorylated AMP kinase. Hence, contrary to popular belief as being beneficial, chronic excess of ω-6 PUFA with its predisposition to induce mitochondrial nitrosative damage and energy deficit, could initiate myocardial dysfunction. Funded by the Heart and Stroke Foundation of BC and Yukon, Canada