Despite aggressive diagnosis and treatment, hypertension remains a major clinical problem and frequently leads to chronic heart failure (HF) The omega-3 fatty acids found in fish oils (eicosapentanoic acid (EPA) and docohexanoic acid (DHA)) and in some plants (1-linolenic acid (ALA) in flax seed or canola oil) may prevent the development of left ventricular (LV) hypertrophy and HF in hypertension. We recently observed that the addition of fish oil (2.8% of energy consumption as EPA+DHA) to the diet of rats subjected to hypertension attenuated LV hypertrophy and prevented the development of LV dysfunction. HF causes down-regulation of peroxisome proliferator activated receptor (PPAR)-regulated genes (which control expression of proteins involved in energy metabolism) and decreases fatty acid metabolism and impairs mitochondrial function. Omega-3 fatty acids are potent ligands for PPARs, and thus could activate cardiac gene expression and improve mitochondrial metabolism and cardiac function. Fish oil intake also increased the cardioprotective hormone adiponectin in plasma, which we found correlated with prevention of cardiac dysfunction in pressure overloaded rats. The goal of this application is to understand how omega-3 fatty acids affect the development and progression of HF in pressure-overload hypertension. Studies will be performed in vivo using well established aortic banding models of LV hypertrophy and HF. Our primary hypothesis is that omega 3FA (either from fish oil or ALA) will attenuate LVH and prevent HF due to increased expression of PPAR-regulated genes and increased serum adiponectin concentration. The two Specific Aims are: 1)Determine the effects of dietary omega 3FA (from either fish oil (EPA+DHA) or flax seed oil (ALA)) on the development of HF during hypertension induced by chronic aortic banding in rats. In addition, the ability of omega 3FA to reverse established HF will be assessed. 2) Determine if increased adiponectin is essential for the prevention of LVH and HF observed with omega 3FA supplementation. WT and adiponectin knock out mice will be subjected to aortic banding and fed either normal chow or chow supplemented with I-3FAs from fish oil. Echocardiography and LV pressure-volume measurements will be used to assess development of hypertrophy and HF, and alterations in gene expression and metabolic enzymes will be measured.

Public Health Relevance

Despite aggressive diagnosis and treatment, hypertension remains a major clinical problem and frequently leads to chronic heart failure. The omega-3 fatty acids found in fish oils and in some plants may prevent the development heart failure. The goal of this application is to understand how omega-3 fatty acids affect the development and progression of HF in hypertension. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HL091307-01A1
Application #
7471865
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Ershow, Abby
Project Start
2008-04-01
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
1
Fiscal Year
2008
Total Cost
$281,250
Indirect Cost
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Khairallah, Ramzi J; Kim, Junhwan; O'Shea, Karen M et al. (2012) Improved mitochondrial function with diet-induced increase in either docosahexaenoic acid or arachidonic acid in membrane phospholipids. PLoS One 7:e34402
Khairallah, Ramzi J; O'Shea, Karen M; Brown, Bethany H et al. (2010) Treatment with docosahexaenoic acid, but not eicosapentaenoic acid, delays Ca2+-induced mitochondria permeability transition in normal and hypertrophied myocardium. J Pharmacol Exp Ther 335:155-62
Khairallah, Ramzi J; Sparagna, Genevieve C; Khanna, Nishanth et al. (2010) Dietary supplementation with docosahexaenoic acid, but not eicosapentaenoic acid, dramatically alters cardiac mitochondrial phospholipid fatty acid composition and prevents permeability transition. Biochim Biophys Acta 1797:1555-62
O'Shea, Karen M; Chess, David J; Khairallah, Ramzi J et al. (2010) ?-3 Polyunsaturated fatty acids prevent pressure overload-induced ventricular dilation and decrease in mitochondrial enzymes despite no change in adiponectin. Lipids Health Dis 9:95
O'Shea, Karen M; Chess, David J; Khairallah, Ramzi J et al. (2010) Effects of adiponectin deficiency on structural and metabolic remodeling in mice subjected to pressure overload. Am J Physiol Heart Circ Physiol 298:H1639-45
Duda, Monika K; O'Shea, Karen M; Tintinu, Anselm et al. (2009) Fish oil, but not flaxseed oil, decreases inflammation and prevents pressure overload-induced cardiac dysfunction. Cardiovasc Res 81:319-27
Chess, David J; Khairallah, Ramzi J; O'Shea, Karen M et al. (2009) A high-fat diet increases adiposity but maintains mitochondrial oxidative enzymes without affecting development of heart failure with pressure overload. Am J Physiol Heart Circ Physiol 297:H1585-93
Shah, Keyur B; Duda, Monika K; O'Shea, Karen M et al. (2009) The cardioprotective effects of fish oil during pressure overload are blocked by high fat intake: role of cardiac phospholipid remodeling. Hypertension 54:605-11
O'Shea, Karen M; Khairallah, Ramzi J; Sparagna, Genevieve C et al. (2009) Dietary omega-3 fatty acids alter cardiac mitochondrial phospholipid composition and delay Ca2+-induced permeability transition. J Mol Cell Cardiol 47:819-27
Duda, Monika K; O'Shea, Karen M; Stanley, William C (2009) omega-3 polyunsaturated fatty acid supplementation for the treatment of heart failure: mechanisms and clinical potential. Cardiovasc Res 84:33-41

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