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The role of individual n-6 polyunsaturated fatty acids on regulating cardiovascular reactivity

University of British Columbia

Linoleic acid (LA), the major dietary n-6 polyunsaturated fatty acid (PUFA) is known to aggravate cardiovascular diseases (CVD) by inducing mitochondrial oxidative damage. Along with mitochondrial damage, CVD patients often have higher LA in blood plasma, as a result of increased dietary LA or its defective removal. We hypothesized that improving mitochondrial oxidative stress can accelerate LA removal, and lower vascular reactivity. Globally blocking LA bioconversion lowered mitochondrial redox potential, and increased the expression of pro-hypertensive adrenergic receptor α-1a in cardiomyocytes (Aim 1) in vitro. Using heterozygous elongase 5 (Elovl5) mice with impaired removal of LA, a higher LA accumulation as well as an increased aortic pressure was identified in Elovl5+/- mice, compared to Elovl5+/+ mice using Pulsed-wave Doppler (Aim 2). Interestingly, limiting LA intake could not overcome the genetic deficiency of Elovl5 and demonstrated similar aortic pressures in mice fed with olive oil. This indicates a crucial role of Elovl5 in maintaining LA concentrations in vivo, as well as vascular reactivity. In addition, Elovl5+/- mice had lower glutathione (GSH) regulating genes in the heart. GSH is a master antioxidant and can alter mitochondrial oxidative damage. Indeed, addition of GSH ethyl ester lowered oxidative stress and improved LA removal in cardiomyocytes in vitro. Next, we used EndoG+/- (endonuclease G) mice, lacking a mitochondrial endonuclease which cleaves mtDNA under oxidative stress. EndoG+/- protected against GSH loss in heart under high n-6 PUFA diet. Such effects were confirmed in vitro when over-expression of EndoG damaged mitochondrial function in fibroblasts treated with LA (Aim 3). In conclusion, accumulation of LA either by dietary or genetic approach potentiates vascular reactivity. We also identified two targets that can potentially lower LA accumulation and vascular and cardiac reactivity, i.e. a) Elovl5 and b) GSH, both of which can protect the mitochondria and ensure LA removal to prevent against CVD.

Text

2019-09-24

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/71761

Biology

University of British Columbia

UBCO

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