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Effect of common dietary fatty acids on viability and fibrosis of cardiac cells

University of British Columbia

Excess dietary fatty acids (FA) are considered a major contributory factor to the high prevalence of type-2 diabetes and cardiac disease. A pathological feature of cardiac disease is cardiac fibrosis. Following cardiomyocyte death, fibroblasts deposit extracellular matrix (ECM) components (fibrosis) to maintain structural integrity of the heart. However, excess fibrosis results in cardiac dysfunction. The current North American diet consists of high levels of polyunsaturated fatty acids (PUFA), mainly linoleic acid (LA; omega-6 PUFA) from vegetable oils such as corn, sunflower and safflower oils. Unlike saturated FAs, the effects of omega-6 PUFAs, like LA, alone and during oxidative stress are not widely studied. Incubation with LA and oleic acid (OA), a monounsaturated FA used as a control, decreased cell viability of cardiomyocytes and fibroblasts. High concentrations of hydrogen peroxide, used to mimic oxidative insult, also reduced cell viability and depleted glutathione, an antioxidant in fibroblasts. Furthermore, during such oxidative insult, high concentrations or longer exposure to FAs exacerbated cell death. While hydrogen peroxide decreased collagen in fibroblasts in combination with FAs, it increased soluble collagen but decreased deposited collagen. TGFβ1-stimulation was used to create a fibrotic stimulus in vitro. TGFβ1 increased soluble and insoluble collagen under low but not high glucose conditions. After TGFβ1-stimulation, LA but not OA increased deposited collagen levels in fibroblasts. In addition, in the presence of LA, the gene expression of fibroblasts demonstrated increased expression of TIMP1, known to inhibit degradation of the ECM. Furthermore, the COL1α1/COL3 ratio, which is directly proportional to fibrotic stiffness, was increased in fibroblasts incubated with LA. In vivo, mice were fed with either corn oil (CO) or olive oil (OO) diets, followed by isoproterenol administration to initiate cardiac injury. OO feeding increased TGFβ3 expression in mice hearts. In addition, similar to in vitro experiments, the COL1α1/COL3 ratio in mice hearts was increased following isoproterenol-induced cardiac injury with CO. These results identified increased LA as a cause of increased collagen deposition and altered TIMP1 expression during fibrosis. The results also point towards an augmented COL1α1/COL3 ratio, which determines cardiac stiffness following fibrosis, which is an important mediator amenable to dietary FAs.

Text

2013-12-02

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/45580

Biology

University of British Columbia

UBCO

http://creativecommons.org/licenses/by-nc-nd/4.0/