Omega-3 Fatty Acids Prevent Pressure Overload–Induced Cardiac Fibrosis Through Activation of Cyclic GMP/Protein Kinase G Signaling in Cardiac Fibroblasts

Chen, Jinghai; Shearer, Gregory C.; Chen, Quanhai; Healy, Chastity L.; Beyer, April J.; Nareddy, V.; Gerdes, A. Martin; Harris, William S.; OʼConnell, Timothy D.; Wang, Dajun

doi:10.1161/circulationaha.110.971853

Cited by 146 publications

(153 citation statements)

References 32 publications

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“…The n-3 polyunsaturated fatty acid supplementation attenuated cardiac hypertrophy and fibrosis and prevented upregulation of genes associated with heart failure in rats. 15,16 In our subjects eating a reduced-carbohydrate diet, sucrose ingestion decreased whereas polyunsaturated fatty acid ingestion increased relative to total energy intake. However, these positive changes in dietary composition may have been counterbalanced by increased saturated fatty acid ingestion.…”

Section: Discussionmentioning

confidence: 82%

“…We suggest that the limited impact of macronutrient composition on LV mass in patients may be explained by the modest carbohydrate or fat restriction compared to dietary manipulations in rodents. 12,13,16 Species differences in the susceptibility to dietary interventions also may be involved.…”

Section: Discussionmentioning

confidence: 99%

“…13,14 In contrast, n-3 polyunsaturated fatty acid supplementation attenuated cardiac hypertrophy and fibrosis in rats. 15,16 Therefore, in addition to caloric intake, macronutrient content and composition could affect LV mass and ventricular function during energy restricted diets. Carbohydrate-restricted and fat-restricted diets are commonly prescribed.…”

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confidence: 99%

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Left Ventricular Mass and Function With Reduced-Fat or Reduced-Carbohydrate Hypocaloric Diets in Overweight and Obese Subjects

et al. 2012

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Abstract-In animals, carbohydrate and fat composition during dietary interventions influenced cardiac metabolism, structure, and function. Because reduced-carbohydrate and reduced-fat hypocaloric diets are commonly used in the treatment of obesity, we investigated whether these interventions differentially affect left ventricular mass, cardiac function, and blood pressure. We randomized 170 overweight and obese subjects (body mass index, 32.9Ϯ4.4; range, 26.5-45.4 kg/m 2 ) to 6-month hypocaloric diets with either reduced carbohydrate intake or reduced fat intake. We obtained cardiac MRI and ambulatory blood pressure recordings over 24 hours before and after 6 months. Ninety subjects completing the intervention period had a full cardiac MRI data set. Subjects lost 7.3Ϯ4.0 kg (7.9Ϯ3.8%) with reduced-carbohydrate diet and 6.2Ϯ4.2 kg (6.7Ϯ4.4%) with reduced-fat diet (PϽ0.001 within each group; Pϭnot significant between interventions). Caloric restriction led to similar significant decreases in left ventricular mass with low-carbohydrate diets (5.4Ϯ5.4 g) or low-fat diets (5.2Ϯ4.8 g; PϽ0.001 within each group; Pϭnot significant between interventions). Systolic and diastolic left ventricular function did not change with either diet. The 24-hour systolic blood pressure decreased similarly with both interventions. Body weight change (␤ϭ0.33; Pϭ0.02) and percentage of ingested n-3 polyunsaturated fatty acids (␤ϭϪ0.27; Pϭ0.03) predicted changes in left ventricular mass. In conclusion, weight loss induced by reduced-fat diets or reduced-carbohydrate diets similarly improved left ventricular mass in overweight and obese subjects over a 6-month period. However, n-3 polyunsaturated fatty acid ingestion may have an independent beneficial effect on left ventricular mass. O besity is associated with increased left ventricular (LV) mass, 1,2 a potential contributor to heart failure, cardiovascular events, and mortality. 3,4 Energy-restricted diets decrease LV mass in conjunction with body weight loss. [5][6][7] In addition to caloric intake, dietary macronutrient composition appears to influence cardiac metabolism, structure, and function, 8 as well as vascular compliance. 9 In animals, high-fat feeding attenuated cardiac hypertrophy and remodeling, 10,11 whereas high-carbohydrate feeding accelerated the process. 12 Excessive simple sugars and saturated fatty acid ingestion worsened cardiac structure and function. 13,14 In contrast, n-3 polyunsaturated fatty acid supplementation attenuated cardiac hypertrophy and fibrosis in rats. 15,16 Therefore, in addition to caloric intake, macronutrient content and composition could affect LV mass and ventricular function during energy restricted diets. Carbohydrate-restricted and fat-restricted diets are commonly prescribed. 17 Whether macronutrient content, without changing physical activity, affects hypocaloric diet-induced changes in LV mass and function has not been investigated in humans. The issue is important given the independent prognostic role of LV mass on cardiovascular events. ...

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

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Left Ventricular Mass and Function With Reduced-Fat or Reduced-Carbohydrate Hypocaloric Diets in Overweight and Obese Subjects

et al. 2012

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“…5 This is supported by several mechanisms: (i) favorable changes in cell membrane lipid composition; 6 (ii) modulation of soluble and cellular inflammatory responses; 7 (iii) modulation of the coagulation cascade, 8 and (iv) production of nitric oxide. 9 The fatty acid profile of the red cell membrane from SCD patients is intrinsically different from that of healthy controls, with a relative increase in the ratio of ω-6 to ω-3 PUFA. 10,11 Sickle erythrocytes have increased ω-6-derived arachidonic acid (20:4n6) and decreased eicosapentaenoic acid (20:5n3) and docosahexaenoic acid (22:6n3).…”

Section: Introductionmentioning

confidence: 99%

Dietary -3 fatty acids protect against vasculopathy in a transgenic mouse model of sickle cell disease

et al. 2015

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The anemia of sickle cell disease is associated with a severe inflammatory vasculopathy and endothelial dysfunction, which leads to painful and life-threatening clinical complications. Growing evidence supports the anti-inflammatory properties of ω-3 fatty acids in clinical models of endothelial dysfunction. Promising but limited studies show potential therapeutic effects of ω-3 fatty acid supplementation in sickle cell disease. Here, we treated humanized healthy and sickle cell mice for 6 weeks with ω-3 fatty acid diet (fish-oil diet). We found that a ω-3 fatty acid diet: (i) normalizes red cell membrane ω-6/ ω-3 ratio; (ii) reduces neutrophil count; (iii) decreases endothelial activation by targeting endothelin-1 and (iv) improves left ventricular outflow tract dimensions. In a hypoxia-reoxygenation model of acute vaso-occlusive crisis, a ω-3 fatty acid diet reduced systemic and local inflammation and protected against sickle cell-related end-organ injury. Using isolated aortas from sickle cell mice exposed to hypoxia-reoxygenation, we demonstrated a direct impact of a ω-3 fatty acid diet on vascular activation, inflammation, and anti-oxidant systems. Our data provide the rationale for ω-3 dietary supplementation as a therapeutic intervention to reduce vascular dysfunction in sickle cell disease. ABSTRACTmice. 16,17 The animal protocol was approved by the Animal Care and Use Committee of the University of Verona (CIRSAL). Twomonth old animals were fed for 6 weeks with either the standard AIN-93M purified rodent diet (soy-diet with n6/n3 ratio of 8:1 -Dyets Inc., Bethlehem, PA, USA), containing 140 g/kg casein, 1.8 g/kg L-cystine, 100 g/kg sucrose, 465.9 g/kg cornstarch, 155 g/kg dextrose, 40 g/kg soybean oil, 0.8 mg/kg t-butylhydroquinone, 50 g/kg cellulose, 35 g/kg mineral mix, 10 g/kg vitamin mix, and 2.5 g/kg choline bitartrate 18 or the ω-3 FD, an AIN-93M-based purified rodent diet in which all of the calories provided by fat (10%) are replaced by 7.9% from HCO and 2.1% from ω-3 oil (Dyets Inc., Bethlehem, PA, USA). At the end of the 6 weeks of FD supplementation, animals were anesthetized with isofluorane, and whole blood was collected from each mouse via retro-orbital venipuncture by heparinized microcapillaries. Mice were euthanized and organs removed immediately. The organs were divided into two and either frozen immediately in liquid nitrogen or fixed in 10% formalin and embedded in paraffin for histology. Whenever indicated, 6-week old mice were exposed to hypoxia (8% oxygen for 10 h) followed by 3 h of reoxygenation (21% oxygen) (H/R stress) to mimic an acute VOC, as previously described.

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“…It has also been reported that n-3 PUFA increases the expression and activation of eNOS, leading to vasodilation 17) . Furthermore, the EPA-induced translocation of eNOS from caveolin in the cell membrane to the cytosol results in the enhancement and activation of the eNOS system and may a cause of EPA-induced vasodilation 18) .…”

Section: Discussionmentioning

confidence: 99%

Effects of Docosahexaenoic Acid on the Endothelial Function in Patients with Coronary Artery Disease

Yagi

Aihara

Fukuda

et al. 2015

JAT

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Aim:The consumption of n-3 polyunsaturated fatty acids (PUFA), including docosahexaenoic acid (DHA), reduces the incidence of cardiovascular events, and reduced serum levels of n-3 PUFA may be associated with an increased risk of cardiovascular events. However, controversy remains regarding which components of PUFA are associated with the endothelial function in patients with coronary artery disease (CAD). We therefore examined the associations between the n-3 and n-6 PUFA levels and CAD. Methods: We retrospectively reviewed 160 consecutive Japanese patients with CAD whose endothelial function was measured according to the percent change in flow-mediated dilation (FMD) and the serum levels of n-3 PUFA, including eicosapentaenoic acid (EPA) and DHA, and n-6 PUFA, including arachidonic acid (AA) and dihomo-gamma-linolenic acid (DHLA). Results: A single regression analysis showed no relationships between the FMD and the serum levels of PUFA, including EPA, DHA, AA and DHLA. In contrast, a multiple regression analysis showed that the DHA level was a positive (P 0.01) and age was a negative (P 0.001) contributor to an increased FMD; however, sex, body mass index, systolic and diastolic blood pressure, current/past smoking and the levels of HbA1c, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, EPA, AA and DHLA did not significantly affect the outcome.

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Omega-3 Fatty Acids Prevent Pressure Overload–Induced Cardiac Fibrosis Through Activation of Cyclic GMP/Protein Kinase G Signaling in Cardiac Fibroblasts

Cited by 146 publications

References 32 publications

Left Ventricular Mass and Function With Reduced-Fat or Reduced-Carbohydrate Hypocaloric Diets in Overweight and Obese Subjects

Left Ventricular Mass and Function With Reduced-Fat or Reduced-Carbohydrate Hypocaloric Diets in Overweight and Obese Subjects

Dietary -3 fatty acids protect against vasculopathy in a transgenic mouse model of sickle cell disease

Effects of Docosahexaenoic Acid on the Endothelial Function in Patients with Coronary Artery Disease

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