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ABSTRACT: Traditional proteomics provides static assessment of protein content, but not synthetic rates. Recently proteome dynamics with heavy water (2H2O) was introduced, where 2H labels amino acids that are incorporated into proteins, and the synthesis rate of individual proteins is calculated using mass isotopomer distribution analysis. We refine this approach with a novel algorithm and rigorous selection criteria that improve the accuracy and precision of the calculation of synthesis rates, and use it to measure protein kinetics in spatially distinct cardiac mitochondrial subpopulations. Subsarcolemmal and interfibrillar mitochondria (SSM and IFM) were isolated from adult rats were given 2H2O in the drinking water for up to 60 days. Plasma 2H2O and myocardial 2H enrichment of amino acids were stable throughout the experimental protocol. Multiple tryptic peptides were identified from 28 proteins in both SSM and IFM, and showed a time-dependent increase in heavy mass isotopomers that was consistent within a given protein. Mitochondrial protein synthesis was relatively slow (average half-life of 30 days, 2.4%/day). Although the synthesis rates for individual proteins were correlated between IFM and SSM (R2=0.84, p<0.0001), values in IFM were 15% less than SSM (P<0.001). In conclusion: 1) Administration of 2H2O results in stable enrichment of the cardiac precursor amino acid pool, 2) using a refined analytical and computational methods coupled with cell fractionation one can measure synthesis rates for cardiac proteins in subcellular compartments in vivo, and 3) protein synthesis is slower in mitochondria located among the myofibrils than in the subsarcolemmal region.
AJP Heart and Circulatory Physiology 03/2013; · 3.71 Impact Factor
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Girma Asemu,
Kelly A O'Connell,
James W Cox,
Errine R Dabkowski,
Wenhong Xu,
Rogerio F Ribeiro,
Kadambari C Shekar,
Peter A Hecker,
Sharad Rastogi,
Hani N Sabbah,
Charles L Hoppel, William C Stanley
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ABSTRACT: Functional differences between subsarcolemmal and interfibrillar cardiac mitochondria (SSM and IFM) have been observed with aging and pathological conditions in rodents. Results are contradictory and there is little information from large animal models. We assessed the respiratory function and resistance to mitochondrial permeability transition (MPT) in SSM and IFM from healthy young (1 year) and old (8 year) female beagles, and in old beagles with hypertension and LV wall thickening induced by 16 weeks of aldosterone infusion. MPT was assessed in SSM and IFM by Ca(2+) retention and swelling. Healthy young and old beagles had similar mitochondrial structure, respiratory function and Ca(2+)-induced MPT within SSM and IFM subpopulations. On the other hand, oxidative capacity and resistance to Ca(2+)-induced MPT were significantly greater in IFM compared to SSM in all groups. Old beagles treated with aldosterone had greater LV wall thickness and worse diastolic filling, but normal LV chamber volume and systolic function. Treatment with aldosterone did not alter mitochondrial respiratory function, but accelerated Ca(2+) -induced MPT in SSM, but not IFM, compared to healthy old and young beagles. In conclusion, in a large animal model oxidative capacity and resistance to MPT was greater in IFM than in SSM. Further, aldosterone infusion increased susceptibility to MPT in SSM, but not IFM. Together this suggests that SSM are less resilient to acute stress than IFM in the healthy heart, and are more susceptible to development of pathology with chronic stress.
AJP Heart and Circulatory Physiology 12/2012; · 3.71 Impact Factor
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ABSTRACT: Glucose 6-phosphate dehydrogenase (G6PD) catalyzes the rate-determining step in the pentose phosphate pathway, and produces NADPH to fuel glutathione recycling. G6PD deficiency is the most common enzyme deficiency in humans, and affects over 400 million people worldwide; however its impact on cardiovascular disease is poorly understood. The glutathione pathway is paramount to antioxidant defense, and G6PD deficient cells do not cope well with oxidative damage. Limited clinical evidence indicates that G6PD deficiency may be associated with hypertension. However, there is also data to support a protective role of G6PD deficiency in decreasing the risk of heart disease and cardiovascular-associated deaths, perhaps through a decrease in cholesterol synthesis. Studies in G6PD deficient (G6PDX) mice are mixed, and provide evidence for both protective and deleterious effects. G6PD deficiency may provide a protective effect through decreasing cholesterol synthesis, superoxide production, and reductive stress. However, recent studies indicate that G6PDX mice are moderately more susceptible to ventricular dilation in response to myocardial infarction or pressure overload-induced heart failure. Further, G6PDX hearts do not recover as well as non-deficient mice when faced with ischemia-reperfusion injury, and G6PDX mice are susceptible to the development of age-associated cardiac hypertrophy. Overall, the limited available data indicate a complex interplay in which adverse effects of G6PD deficiency may outweigh potential protective effects in the face of cardiac stress. Definitive clinical studies in large populations are needed to determine the effects of G6PD deficiency on the development of cardiovascular disease and subsequent outcomes.
AJP Heart and Circulatory Physiology 12/2012; · 3.71 Impact Factor
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Peter A Hecker,
Vincenzo Lionetti,
Rogerio F Ribeiro,
Sharad Rastogi,
Bethany H Brown,
Kelly A O'Connell,
James W Cox,
Kadambari C Shekar,
Dionna Gamble,
Hani N Sabbah,
Jane A Leopold,
Sachin A Gupte,
Fabio A Recchia, William C Stanley
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ABSTRACT: BACKGROUND: -Glucose 6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme deficiency in the world. In failing hearts, G6PD is upregulated and generates NADPH that is used by the glutathione pathway to remove reactive oxygen species (ROS), but also as a substrate by ROS-generating enzymes. Therefore, G6PD deficiency might prevent heart failure by decreasing NADPH and ROS production. METHODS AND RESULTS: -This hypothesis was evaluated in a mouse model of human G6PD deficiency (G6PDX mice, ~40% normal activity). Myocardial infarction with 3 months follow-up resulted in LV dilation and dysfunction in both WT and G6PDX mice, but significantly greater end diastolic volume and wall thinning in G6PDX mice. Similarly, pressure overload induced by transverse aortic constriction (TAC) for 6 weeks caused greater LV dilation in G6PDX mice than WT. We further stressed TAC mice by feeding a high fructose diet to increase flux through G6PD and ROS production, and again observed worse LV remodeling and a lower ejection fraction in G6PDX than WT mice. Tissue content of lipid peroxidation products was increased in G6PDX mice in response to infarction and aconitase activity was decreased with TAC, suggesting that G6PD deficiency increases myocardial oxidative stress and subsequent damage. CONCLUSIONS: -Contrary to our hypothesis, G6PD deficiency increased redox stress in response to infarction or pressure overload. However, we found only a modest acceleration of LV remodeling, suggesting that, in individuals with G6PD deficiency and concurrent hypertension or myocardial infarction, the risk for developing heart failure is higher, but limited by compensatory mechanisms.
Circulation Heart Failure 11/2012; · 6.29 Impact Factor
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Tatianaa F Galvao,
Ramzi J Khairallah,
Erinne R Dabkowski,
Bethany H Brown,
Peter A Hecker,
Kelly A O'Connell,
Karen M O'Shea,
Hani N Sabbah,
Sharad Rastogi,
Caroline Daneault,
Christine Des Rosiers, William C Stanley
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ABSTRACT: Mitochondrial dysfunction in heart failure includes greater susceptibility to mitochondrial permeability transition, which may worsen cardiac function and decrease survival. Treatment with a mixture of the n3 polyunsaturated fatty acids (n3 PUFA) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) is beneficial in heart failure patients, and increases resistance to mitochondrial permeability transition in animal models. We assessed if DHA and EPA have similar effects when given individually, and if they prolong survival in heart failure. Male δ-sarcoglycan null cardiomyopathic hamsters were untreated or given either DHA, EPA or a 1:1 mixture of DHA+EPA at 2.1% of energy intake. Treatment did not prolong survival: mean survival was 298±15 days in untreated hamsters, and was 335±17, 328±14 and 311±15 days with DHA, EPA and DHA+EPA, respectively (n=27-32/group). A subgroup of cardiomyopathic hamsters treated for 26 weeks had impaired LV function and increased cardiomyocyte apoptosis compared to normal hamsters, which was unaffected by n3 PUFA treatment. Evaluation of oxidative phosphorylation in isolated subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria with substrates for complex I or II showed no effect of n3 PUFA treatment. On the other hand, IFM from cardiomyopathic hamsters were significantly more sensitive to Ca(2+)-induced mitochondrial permeability transition, which was completely normalized by treatment with DHA, and partial corrected by EPA. In conclusion, treatment with DHA or EPA normalizes Ca(2+)-induced MPT in cardiomyopathic hamsters, but does not prolong survival or improve cardiac function.
AJP Heart and Circulatory Physiology 10/2012; · 3.71 Impact Factor
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ABSTRACT: The effects of vagal stimulation (VS) on cardiac energy substrate metabolism are unknown. We tested the hypothesis that acute VS alters the balance between free fatty acid (FFA) and carbohydrate oxidation and opposes the metabolic effects of beta-adrenergic stimulation. A clinical-type selective stimulator of the vagal efferent fibers was connected to the intact right vagus in chronically instrumented dogs. VS was set to reduce heart rate by 30 beats min-1, then the confounding effects of bradycardia were eliminated by pacing the heart at 165 beats min-1. 3H-oleate and 14C-glucose were infused to measure FFA and glucose oxidation. The heart was subjected to beta-adrenergic stress by infusing 5, 10 and 15 µg kg-1 min-1 of dobutamine before and during VS. We found that VS did not significantly affect baseline cardiac performance, haemodynamics and myocardial metabolism. However, at peak dobutamine stress, VS attenuated the increase in left ventricular pressure-diameter area from 235.9±72.8% to 167.3±55.8%, and in cardiac oxygen consumption from 173.9±23.3% to 127.89±6.2% (both P<0.05), thus mechanical efficiency was not enhanced. The increase in glucose oxidation fell from 289.3%±55.5 to 131.1±20.9 (both P<0.05), while FFA oxidation was not increased by beta-adrenergic stress and fell below baseline during VS only at the lowest dose of dobutamine. The functional and in part the metabolic changes were reversed by 0.1 mg kg-1 atropine I.V. Our data show that acute right VS does not affect baseline cardiac metabolism, but attenuates myocardial oxygen consumption and glucose oxidation in response adrenergic stress, thus functioning as a cardio-selective antagonist to beta-adrenergic activation.
The Journal of Physiology 09/2012; · 4.72 Impact Factor
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ABSTRACT: Rationale: At birth, there is a switch from placental to pulmonary circulation and the heart commences its aerobic metabolism. In cardiac myocytes, this transition is marked by increased mitochondrial biogenesis and remodeling of the intracellular architecture. The mechanisms governing the formation of new mitochondria and their expansion within myocytes remain largely unknown. Mitofusins (Mfn-1 and Mfn-2) are known regulators of mitochondrial networks, but their role during perinatal maturation of the heart has yet to be examined. Objective: The objective of this study was to determine the significance of mitofusins during early postnatal cardiac development. Methods and Results: We genetically inactivated Mfn-1 and Mfn-2 in midgestational and postnatal cardiac myocytes using a loxP/Myh6-cre approach. At birth, cardiac morphology and function of double-knockout (DKO) mice are normal. At that time, DKO mitochondria increase in numbers, appear to be spherical and heterogeneous in size, but exhibit normal electron density. By postnatal day 7, the mitochondrial numbers in DKO myocytes remain abnormally expanded and many lose matrix components and membrane organization. At this time point, DKO mice have developed cardiomyopathy. This leads to a rapid decline in survival and all DKO mice die before 16 days of age. Gene expression analysis of DKO hearts shows that mitochondria biogenesis genes are downregulated, the mitochondrial DNA is reduced, and mitochondrially encoded transcripts and proteins are also reduced. Furthermore, mitochondrial turnover pathways are dysregulated. Conclusions: Our findings establish that Mfn-1 and Mfn-2 are essential in mediating mitochondrial remodeling during postnatal cardiac development, a time of dramatic transitions in the bioenergetics and growth of the heart.
Circulation Research 08/2012; 111(8):1012-26. · 9.49 Impact Factor
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Peter A Hecker,
Rudo F Mapanga,
Charlene P Kimar,
Rogerio F Ribeiro,
Bethany H Brown,
Kelly A O'Connell,
James W Cox,
Kadambari C Shekar,
Girma Asemu,
M Faadiel Essop, William C Stanley
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ABSTRACT: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common human enzymopathy that affects cellular redox status and may lower flux into nonoxidative pathways of glucose metabolism. Oxidative stress may worsen systemic glucose tolerance and cardiometabolic syndrome. We hypothesized that G6PD deficiency exacerbates diet-induced systemic metabolic dysfunction by increasing oxidative stress but in myocardium prevents diet-induced oxidative stress and pathology. WT and G6PD-deficient (G6PDX) mice received a standard high-starch diet, a high-fat/high-sucrose diet to induce obesity (DIO), or a high-fructose diet. After 31 wk, DIO increased adipose and body mass compared with the high-starch diet but to a greater extent in G6PDX than WT mice (24 and 20% lower, respectively). Serum free fatty acids were increased by 77% and triglycerides by 90% in G6PDX mice, but not in WT mice, by DIO and high-fructose intake. G6PD deficiency did not affect glucose tolerance or the increased insulin levels seen in WT mice. There was no diet-induced hypertension or cardiac dysfunction in either mouse strain. However, G6PD deficiency increased aconitase activity by 42% and blunted markers of nonoxidative glucose pathway activation in myocardium, including the hexosamine biosynthetic pathway activation and advanced glycation end product formation. These results reveal a complex interplay between diet-induced metabolic effects and G6PD deficiency, where G6PD deficiency decreases weight gain and hyperinsulinemia with DIO, but elevates serum free fatty acids, without affecting glucose tolerance. On the other hand, it modestly suppressed indexes of glucose flux into nonoxidative pathways in myocardium, suggesting potential protective effects.
AJP Endocrinology and Metabolism 07/2012; 303(8):E959-72. · 4.75 Impact Factor
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ABSTRACT: We investigated whether chronic in vivo treatment with the peroxisome proliferator-activated receptor α agonist Wy-14,643
attenuates cardiac contractile function by impairing mitochondrial respiration. Wy-14,643 (25mgkg−1day−1) was administered to Wistar rats by oral gavage for 14 consecutive days, after which ex vivo heart function, myocardial mitochondrial
respiratory capacity, and metabolic gene expression were determined. Body and heart weights were not significantly altered
following 14days of Wy-14,643 administration. Heart perfusion studies showed significantly reduced systolic and developed
pressures, while the rate pressure product declined by 36±2.6% (P<0.01 vs. vehicle) after 14days of Wy-14,643 treatment. State 3 mitochondrial respiration was lower in the Wy-14,643 group
(P=0.06 vs. vehicle). State 4 respiration and oligomycin-insensitive proton leak were significantly increased compared with
matched controls. The rate of ADP phosphorylation was also decreased by 44.9±1.9% (P<0.05 vs. vehicle). Pyruvate dehydrogenase kinase 4 (PDK4) and uncoupling protein 3 (UCP3) transcript levels were upregulated,
while cytochrome oxidase II (COXII) expression was decreased following Wy-14,643 treatment. This study demonstrates that chronic
in vivo Wy-14,643 administration impaired cardiac contractile function in parallel with decreased mitochondrial respiratory
function and increased uncoupling.
Molecular and Cellular Biochemistry 04/2012; 330(1):55-62. · 2.06 Impact Factor
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ABSTRACT: Understanding the pathologies related to the regulation of protein metabolism requires methods for studying the kinetics of individual proteins. We developed a (2)H(2)O metabolic labeling technique and software for protein kinetic studies in free living organisms. This approach for proteome dynamic studies requires the measurement of total body water enrichments by GC-MS, isotopic distribution of the tryptic peptide by LC-MS/MS, and estimation of the asymptotical number of deuterium incorporated into a peptide by software. We applied this technique to measure the synthesis rates of several plasma lipoproteins and acute phase response proteins in rats. Samples were collected at different time points, and proteins were separated by a gradient gel electrophoresis. (2)H labeling of tryptic peptides was analyzed by ion trap tandem mass spectrometry (LTQ MS/MS) for measurement of the fractional synthesis rates of plasma proteins. The high sensitivity of LTQ MS in zoom scan mode in combination with (2)H label amplification in proteolytic peptides allows detection of the changes in plasma protein synthesis related to animal nutritional status. Our results demonstrate that fasting has divergent effects on the rate of synthesis of plasma proteins, increasing synthesis of ApoB 100 but decreasing formation of albumin and fibrinogen. We conclude that this technique can effectively measure the synthesis of plasma proteins and can be used to study the regulation of protein homeostasis under physiological and pathological conditions.
Molecular & Cellular Proteomics 03/2012; 11(7):M111.014209. · 7.40 Impact Factor
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ABSTRACT: There is growing evidence suggesting that dietary fat intake affects the development and progression of heart failure. Studies in rodents show that in the absence of obesity, replacing refined carbohydrate with fat can attenuate or prevent ventricular expansion and contractile dysfunction in response to hypertension, infarction, or genetic cardiomyopathy. Relatively low intake of n-3 polyunsaturated fatty acids from marine sources alters cardiac membrane phospholipid fatty acid composition, decreases the onset of new heart failure, and slows the progression of established heart failure. This effect is associated with decreased inflammation and improved resistance to mitochondrial permeability transition. High intake of saturated, monounsaturated, or n-6 polyunsaturated fatty acids has also shown beneficial effects in rodent studies. The underlying mechanisms are complex, and a more thorough understanding is needed of the effects on cardiac phospholipids, lipid metabolites, and metabolic flux in the normal and failing heart. In summary, manipulation of dietary fat intake shows promise in the prevention and treatment of heart failure. Clinical studies generally support high intake of n-3 polyunsaturated fatty acids from marine sources to prevent and treat heart failure. Additional clinical and animals studies are needed to determine the optimal diet in terms of saturated, monounsaturated, and n-6 polyunsaturated fatty acids intake for this vulnerable patient population.
Circulation Research 03/2012; 110(5):764-76. · 9.49 Impact Factor
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ABSTRACT: Recent evidence has linked n-3 polyunsaturated fatty acid (PUFA) supplementation with dramatic alterations of mitochondrial phospholipid membranes and favorable changes in mitochondrial function. In the present review, we examine the novel effects of n-3 PUFA on mitochondria, with an emphasis on cardiac mitochondrial phospholipids.
There is growing evidence that dietary n-3 PUFA, particularly docosahexaenoic acid (DHA), has profound effects on mitochondrial membrane phospholipid composition and mitochondrial function. Supplementation with n-3 PUFA increases membrane phospholipid DHA and depletes arachidonic acid, and can increase cardiolipin, a tetra-acyl phospholipid that is unique to mitochondrial and essential for optimal mitochondrial function. Recent studies show that supplementation with DHA decreases propensity for cardiac mitochondria to undergo permeability transition, a catastrophic event often leading to cell death. This finding provides a potential mechanism for the cardioprotective effect of DHA. Interestingly, other n-3 PUFAs that modify membrane composition to a lesser extent have substantially less of an effect on mitochondria and do not appear to directly protect the heart.
Current data support a role for n-3 PUFA supplementation, particularly DHA, on mitochondria that are strongly associated with changes in mitochondrial phospholipid composition.
Current opinion in clinical nutrition and metabolic care. 03/2012; 15(2):122-6.
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ABSTRACT: A high-sugar intake increases heart disease risk in humans. In animals, sugar intake accelerates heart failure development by increased reactive oxygen species (ROS). Glucose-6-phosphate dehydrogenase (G6PD) can fuel ROS production by providing reduced nicotinamide adenine dinucleotide phosphate (NADPH) for superoxide generation by NADPH oxidase. Conversely, G6PD also facilitates ROS scavenging using the glutathione pathway. We hypothesized that a high-sugar intake would increase flux through G6PD to increase myocardial NADPH and ROS and accelerate cardiac dysfunction and death.
Six-week-old TO-2 hamsters, a non-hypertensive model of genetic cardiomyopathy caused by a δ-sarcoglycan mutation, were fed a long-term diet of high starch or high sugar (57% of energy from sucrose plus fructose).
After 24 wk, the δ-sarcoglycan-deficient animals displayed expected decreases in survival and cardiac function associated with cardiomyopathy (ejection fraction: control 68.7 ± 4.5%, TO-2 starch 46.1 ± 3.7%, P < 0.05 for TO-2 starch versus control; TO-2 sugar 58.0 ± 4.2%, NS, versus TO-2 starch or control; median survival: TO-2 starch 278 d, TO-2 sugar 318 d, P = 0.133). Although the high-sugar intake was expected to exacerbate cardiomyopathy, surprisingly, there was no further decrease in ejection fraction or survival with high sugar compared with starch in cardiomyopathic animals. Cardiomyopathic animals had systemic and cardiac metabolic abnormalities (increased serum lipids and glucose and decreased myocardial oxidative enzymes) that were unaffected by diet. The high-sugar intake increased myocardial superoxide, but NADPH and lipid peroxidation were unaffected.
A sugar-enriched diet did not exacerbate ventricular function, metabolic abnormalities, or survival in heart failure despite an increase in superoxide production.
Nutrition 02/2012; 28(5):520-6. · 3.03 Impact Factor
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ABSTRACT: Molecular studies examining the impact of mitochondrial morphology on the mammalian heart have previously focused on dynamin related protein-1 (Drp-1) and mitofusin-2 (Mfn-2), while the role of the other mitofusin isoform, Mfn-1, has remained largely unexplored. In the present study, we report the generation and initial characterization of cardiomyocyte-specific Mfn-1 knockout (Mfn-1 KO) mice. Using electron microscopic analysis, we detect a greater prevalence of small, spherical mitochondria in Mfn-1 KO hearts, indicating that the absence of Mfn-1 causes a profound shift in the mitochondrial fusion/fission balance. Nevertheless, Mfn-1 KO mice exhibit normal left-ventricular function, and isolated Mfn-1 KO heart mitochondria display a normal respiratory repertoire. Mfn-1 KO myocytes are protected from mitochondrial depolarization and exhibit improved viability when challenged with reactive oxygen species (ROS) in the form of hydrogen peroxide (H(2)O(2)). Furthermore, in vitro studies detect a blunted response of KO mitochondria to undergo peroxide-induced mitochondrial permeability transition pore opening. These data suggest that Mfn-1 deletion confers protection against ROS-induced mitochondrial dysfunction. Collectively, we suggest that mitochondrial fragmentation in myocytes is not sufficient to induce heart dysfunction or trigger cardiomyocyte death. Additionally, our data suggest that endogenous levels of Mfn-1 can attenuate myocyte viability in the face of an imminent ROS overload, an effect that could be associated with the ability of Mfn-1 to remodel the outer mitochondrial membrane.
AJP Heart and Circulatory Physiology 01/2012; 302(1):H167-79. · 3.71 Impact Factor
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Ramzi J Khairallah,
Junhwan Kim,
Karen M O'Shea,
Kelly A O'Connell,
Bethany H Brown,
Tatiana Galvao,
Caroline Daneault,
Christine Des Rosiers,
Brian M Polster,
Charles L Hoppel, William C Stanley
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ABSTRACT: Mitochondria can depolarize and trigger cell death through the opening of the mitochondrial permeability transition pore (MPTP). We recently showed that an increase in the long chain n3 polyunsaturated fatty acids (PUFA) docosahexaenoic acid (DHA; 22:6n3) and depletion of the n6 PUFA arachidonic acid (ARA; 20:4n6) in mitochondrial membranes is associated with a greater Ca(2+) load required to induce MPTP opening. Here we manipulated mitochondrial phospholipid composition by supplementing the diet with DHA, ARA or combined DHA+ARA in rats for 10 weeks. There were no effects on cardiac function, or respiration of isolated mitochondria. Analysis of mitochondrial phospholipids showed DHA supplementation increased DHA and displaced ARA in mitochondrial membranes, while supplementation with ARA or DHA+ARA increased ARA and depleted linoleic acid (18:2n6). Phospholipid analysis revealed a similar pattern, particularly in cardiolipin. Tetralinoleoyl cardiolipin was depleted by 80% with ARA or DHA+ARA supplementation, with linoleic acid side chains replaced by ARA. Both the DHA and ARA groups had delayed Ca(2+)-induced MPTP opening, but the DHA+ARA group was similar to the control diet. In conclusion, alterations in mitochondria membrane phospholipid fatty acid composition caused by dietary DHA or ARA was associated with a greater cumulative Ca(2+) load required to induced MPTP opening. Further, high levels of tetralinoleoyl cardiolipin were not essential for normal mitochondrial function if replaced with very-long chain n3 or n6 PUFAs.
PLoS ONE 01/2012; 7(3):e34402. · 4.09 Impact Factor
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ABSTRACT: The impact of a high-fat diet on the failing heart is unclear, and the differences between polyunsaturated fatty acids (PUFA) and saturated fat have not been assessed. Here, we compared a standard low-fat diet to high-fat diets enriched with either saturated fat (palmitate and stearate) or PUFA (linoleic and α-linolenic acids) in hamsters with genetic cardiomyopathy.
Male δ-sarcoglycan null Bio TO2 hamsters were fed a standard low-fat diet (12% energy from fat), or high-fat diets (45% fat) comprised of either saturated fat or PUFA. The median survival was increased by the high saturated fat diet (P< 0.01; 278 days with standard diet and 361 days with high saturated fat)), but not with high PUFA (260 days) (n = 30-35/group). Body mass was modestly elevated (∼10%) in both high fat groups. Subgroups evaluated after 24 weeks had similar left ventricular chamber size, function, and mass. Mitochondrial oxidative enzyme activity and the yield of interfibrillar mitochondria (IFM) were decreased to a similar extent in all TO2 groups compared with normal F1B hamsters. Ca(2+)-induced mitochondrial permeability transition pore opening was enhanced in IFM in all TO2 groups compared with F1B hamsters, but to a significantly greater extent in those fed the high PUFA diet compared with the standard or high saturated fat diet.
These results show that a high intake of saturated fat improves survival in heart failure compared with a high PUFA diet or low-fat diet, despite persistent mitochondrial defects.
Cardiovascular research 09/2011; 93(1):24-32. · 5.80 Impact Factor
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ABSTRACT: In the advanced stages of heart failure, many key enzymes involved in myocardial energy substrate metabolism display various degrees of down-regulation. The net effect of the altered metabolic phenotype consists of reduced cardiac fatty oxidation, increased glycolysis and glucose oxidation, and rigidity of the metabolic response to changes in workload. Is this metabolic shift an adaptive mechanism that protects the heart or a maladaptive process that accelerates structural and functional derangement? The question remains open; however, the metabolic remodelling of the failing heart has induced a number of investigators to test the hypothesis that pharmacological modulation of myocardial substrate utilization might prove therapeutically advantageous. The present review addresses the effects of indirect and direct modulators of fatty acid (FA) oxidation, which are the best pharmacological agents available to date for 'metabolic therapy' of failing hearts. Evidence for the efficacy of therapeutic strategies based on modulators of FA metabolism is mixed, pointing to the possibility that the molecular/biochemical alterations induced by these pharmacological agents are more complex than originally thought. Much remains to be understood; however, the beneficial effects of molecules such as perhexiline and trimetazidine in small clinical trials indicate that this promising therapeutic strategy is worthy of further pursuit.
Cardiovascular research 02/2011; 90(2):202-9. · 5.80 Impact Factor
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Kyriakos N Papanicolaou,
Ramzi J Khairallah,
Gladys A Ngoh,
Aristide Chikando,
Ivan Luptak,
Karen M O'Shea,
Dushon D Riley,
Jesse J Lugus,
Wilson S Colucci,
W Jonathan Lederer, William C Stanley,
Kenneth Walsh
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ABSTRACT: Mitofusin-2 (Mfn-2) is a dynamin-like protein that is involved in the rearrangement of the outer mitochondrial membrane. Research using various experimental systems has shown that Mfn-2 is a mediator of mitochondrial fusion, an evolutionarily conserved process responsible for the surveillance of mitochondrial homeostasis. Here, we find that cardiac myocyte mitochondria lacking Mfn-2 are pleiomorphic and have the propensity to become enlarged. Consistent with an underlying mild mitochondrial dysfunction, Mfn-2-deficient mice display modest cardiac hypertrophy accompanied by slight functional deterioration. The absence of Mfn-2 is associated with a marked delay in mitochondrial permeability transition downstream of Ca(2+) stimulation or due to local generation of reactive oxygen species (ROS). Consequently, Mfn-2-deficient adult cardiomyocytes are protected from a number of cell death-inducing stimuli and Mfn-2 knockout hearts display better recovery following reperfusion injury. We conclude that in cardiac myocytes, Mfn-2 controls mitochondrial morphogenesis and serves to predispose cells to mitochondrial permeability transition and to trigger cell death.
Molecular and cellular biology 01/2011; 31(6):1309-28. · 6.06 Impact Factor
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ABSTRACT: Intracardiac lipid accumulation can cause heart failure. A study in Journal of Clinical Investigation (Son et al., 2010) found that cardiac-specific PPARγ overexpression caused heart failure with intracardiac triglyceride accumulation. Overexpressing PPARγ on a PPARα-/- background improved cardiac function, suggesting that specific lipid metabolites and lipid packaging determine cardiac lipotoxicity.
Cell metabolism 12/2010; 12(6):555-6. · 17.35 Impact Factor
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ABSTRACT: Intake of fish oil containing docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) prevents heart failure; however, the mechanisms are unclear. Mitochondrial permeability transition pore (MPTP) opening contributes to myocardial pathology in cardiac hypertrophy and heart failure, and treatment with DHA + EPA delays MPTP opening. Here, we assessed: 1) whether supplementation with both DHA and EPA is needed for optimal prevention of MPTP opening, and 2) whether this benefit occurs in hypertrophied myocardium. Rats with either normal myocardium or cardiac hypertrophy induced by 8 weeks of abdominal aortic banding were fed one of four diets: control diet without DHA or EPA or diets enriched with either DHA, EPA, or DHA + EPA (1:1 ratio) at 2.5% of energy intake for 17 weeks. Aortic banding caused a 27% increase in left ventricular mass and 25% depletion in DHA in mitochondrial phospholipids in rats fed the control diet. DHA supplementation raised DHA in phospholipids ∼2-fold in both normal and hypertrophied hearts and increased EPA. DHA + EPA supplementation also increased DHA, but to a lesser extent than DHA alone. EPA supplementation increased EPA, but did not affect DHA compared with the control diet. Ca(2+)-induced MPTP opening was delayed by DHA and DHA + EPA supplementation in both normal and hypertrophied hearts, but EPA had no effect on MPTP opening. These results show that supplementation with DHA alone effectively increases both DHA and EPA in cardiac mitochondrial phospholipids and delays MPTP and suggest that treatment with DHA + EPA offers no advantage over DHA alone.
Journal of Pharmacology and Experimental Therapeutics 10/2010; 335(1):155-62. · 3.83 Impact Factor
