Docosahexaenoic Acid Supplementation Alters Key Properties of Cardiac Mitochondria and Modestly Attenuates Development of Left Ventricular Dysfunction in Pressure Overload-Induced Heart Failure
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Supplementation with the n3 polyunsaturated fatty acid docosahexaenoic acid (DHA) is beneficial in heart failure patients, however the mechanisms are unclear. DHA is incorporated into membrane phospholipids, which may prevent mitochondrial dysfunction. Thus we assessed the effects of DHA supplementation on cardiac mitochondria and the development of heart failure caused by aortic pressure overload.
Pathological cardiac hypertrophy was generated in rats by thoracic aortic constriction. Animals were fed either a standard diet or were supplemented with DHA (2.3 % of energy intake).
After 14 weeks, heart failure was evident by left ventricular hypertrophy and chamber enlargement compared to shams. Left ventricle fractional shortening was unaffected by DHA treatment in sham animals (44.1 ± 1.6 % vs. 43.5 ± 2.2 % for standard diet and DHA, respectively), and decreased with heart failure in both treatment groups, but to a lesser extent in DHA treated animals (34.9 ± 1.7 %) than with the standard diet (29.7 ± 1.5 %, P < 0.03). DHA supplementation increased DHA content in mitochondrial phospholipids and decreased membrane viscosity. Myocardial mitochondrial oxidative capacity was decreased by heart failure and unaffected by DHA. DHA treatment enhanced Ca2+ uptake by subsarcolemmal mitochondria in both sham and heart failure groups. Further, DHA lessened Ca2+-induced mitochondria swelling, an index of permeability transition, in heart failure animals. Heart failure increased hydrogen peroxide-induced mitochondrial permeability transition compared to sham, which was partially attenuated in interfibrillar mitochondria by treatment with DHA.
DHA decreased mitochondrial membrane viscosity and accelerated Ca2+ uptake, and attenuated susceptibility to mitochondrial permeability transition and development of left ventricular dysfunction.
KeywordsCardiac failure Metabolism Polyunsaturated fatty acids Reactive oxygen species
This work was supported by the National Institutes of Health, National Heart Lung and Blood Institute [Grant numbers HL074237, HL110731 and HL101434] .
Conflict of Interest
William Stanley is the inventor on a US patent application filed by the University of Maryland for the use of DHA for the treatment of heart failure. All other authors have no conflicts.
- 4.Moertl D, Hammer A, Steiner S, Hutuleac R, Vonbank K, Berger R. Dose-dependent effects of omega-3-polyunsaturated fatty acids on systolic left ventricular function, endothelial function, and markers of inflammation in chronic heart failure of nonischemic origin: a double-blind, placebo-controlled, 3-arm study. Am Heart J. 2011;161:915–9.PubMedCrossRefGoogle Scholar
- 7.Khairallah RJ, Sparagna GC, Khanna N, O’shea KM, Hecker PA, Kristian T, et al. Dietary supplementation with docosahexaenoic acid, but not eicosapentaenoic acid, dramatically alters cardiac mitochondrial phospholipid fatty acid composition and prevents permeability transition. Biochim Biophys Acta. 2010;1797:1555–62.PubMedCrossRefGoogle Scholar
- 8.Khairallah RJ, O’shea KM, Brown BH, Khanna N, des Rosiers C, Stanley WC. Treatment with docosahexaenoic acid, but not eicosapentaenoic acid, delays Ca2+−induced mitochondria permeability transition in normal and hypertrophied myocardium. J Pharmacol Exp Ther. 2010;335:155–62.PubMedCrossRefGoogle Scholar
- 30.Faerber G, Barreto-Perreia F, Schoepe M, Gilsbach R, Schrepper A, Schwarzer M, et al. Induction of heart failure by minimally invasive aortic constriction in mice: reduced peroxisome proliferator-activated receptor gamma coactivator levels and mitochondrial dysfunction. J Thorac Cardiovasc Surg. 2011;141(492–500):500.Google Scholar
- 34.Papanicolaou KN, Ngoh GA, Dabkowski ER, O’Connell KA, Ribeiro RF, Stanley WC, et al. Cardiomyocyte deletion of mitofusin-1 leads to mitochondrial fragmentation and improves tolerance to ROS-induced mitochondrial dysfunction and cell death. Am J Physiol Heart Circ Physiol. 2012;302:H167–79.PubMedCrossRefGoogle Scholar