RESUMEN

Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by loss of α-motor neurons, leading to profound skeletal muscle atrophy. Patients also suffer from decreased bone mineral density and increased fracture risk. The majority of treatments for SMA, approved or in clinic trials, focus on addressing the underlying cause of disease, insufficient production of full-length SMN protein. While restoration of SMN has resulted in improvements in functional measures, significant deficits remain in both mice and SMA patients following treatment. Motor function in SMA patients may be additionally improved by targeting skeletal muscle to reduce atrophy and improve muscle strength. Inhibition of myostatin, a negative regulator of muscle mass, offers a promising approach to increase muscle function in SMA patients. Here we demonstrate that muSRK-015P, a monoclonal antibody which specifically inhibits myostatin activation, effectively increases muscle mass and function in two variants of the pharmacological mouse model of SMA in which pharmacologic restoration of SMN has taken place either 1 or 24 days after birth to reflect early or later therapeutic intervention. Additionally, muSRK-015P treatment improves the cortical and trabecular bone phenotypes in these mice. These data indicate that preventing myostatin activation has therapeutic potential in addressing muscle and bone deficiencies in SMA patients. An optimized variant of SRK-015P, SRK-015, is currently in clinical development for treatment of SMA.

Asunto(s)

Atrofia Muscular Espinal/genética , Miostatina/genética , Miostatina/fisiología , Animales , Anticuerpos Monoclonales , Modelos Animales de Enfermedad , Ratones , Neuronas Motoras/metabolismo , Fuerza Muscular/fisiología , Músculo Esquelético/metabolismo , Atrofia Muscular Espinal/fisiopatología , Miostatina/antagonistas & inhibidores , Proteína 1 para la Supervivencia de la Neurona Motora/genética , Proteína 2 para la Supervivencia de la Neurona Motora/genética

RESUMEN

Athletes as well as elderly or hospitalized patients use dietary protein supplementation to maintain or grow skeletal muscle. It is recognized that high quality protein is needed for muscle accretion, and can be obtained from both animal and plant-based sources. There is interest to understand whether these sources differ in their ability to maintain or stimulate muscle growth and function. In this study, baseline muscle performance was assessed in 50 adult Sprague-Dawley rats after which they were assigned to one of five semi-purified "Western" diets (n = 10/group) differing only in protein source, namely 19 kcal% protein from either milk protein isolate (MPI), whey protein isolate (WPI), soy protein isolate (SPI), soy protein concentrate (SPC) or enzyme-treated soy protein (SPE). The diets were fed for 8 weeks at which point muscle performance testing was repeated and tissues were collected for analysis. There was no significant difference in food consumption or body weights over time between the diet groups nor were there differences in terminal organ and muscle weights or in serum lipids, creatinine or myostatin. Compared with MPI-fed rats, rats fed WPI and SPC displayed a greater maximum rate of contraction using the in vivo measure of muscle performance (p<0.05) with increases ranging from 13.3-27.5% and 22.8-29.5%, respectively at 60, 80, 100 and 150 Hz. When the maximum force was normalized to body weight, SPC-fed rats displayed increased force compared to MPI (p<0.05), whereas when normalized to gastrocnemius weight, WPI-fed rats displayed increased force compared to MPI (p<0.05). There was no difference between groups using in situ muscle performance. In conclusion, soy protein consumption, in high-fat diet, resulted in muscle function comparable to whey protein and improved compared to milk protein. The benefits seen with soy or whey protein were independent of changes in muscle mass or fiber cross-sectional area.

Asunto(s)

Proteínas en la Dieta/administración & dosificación , Suplementos Dietéticos , Músculo Esquelético/fisiología , Animales , Peso Corporal , Masculino , Músculo Esquelético/crecimiento & desarrollo , Ratas , Ratas Sprague-Dawley

RESUMEN

The biochemical, ionic, and signaling changes that occur within cardiomyocytes subjected to ischemia are exacerbated by reperfusion; however, the precise mechanisms mediating myocardial ischemia/reperfusion (I/R) injury have not been fully elucidated. The receptor for advanced glycation end-products (RAGE) regulates the cellular response to cardiac tissue damage in I/R, an effect potentially mediated by the binding of the RAGE cytoplasmic domain to the diaphanous-related formin, DIAPH1. The aim of this study was to investigate the role of DIAPH1 in the physiological response to experimental myocardial I/R in mice. After subjecting wild-type mice to experimental I/R, myocardial DIAPH1 expression was increased, an effect that was echoed following hypoxia/reoxygenation (H/R) in H9C2 and AC16 cells. Further, compared to wild-type mice, genetic deletion of Diaph1 reduced infarct size and improved contractile function after I/R. Silencing Diaph1 in H9C2 cells subjected to H/R downregulated actin polymerization and serum response factor-regulated gene expression. Importantly, these changes led to increased expression of sarcoplasmic reticulum Ca2+ ATPase and reduced expression of the sodium calcium exchanger. This work demonstrates that DIAPH1 is required for the myocardial response to I/R, and that targeting DIAPH1 may represent an adjunctive approach for myocardial salvage after acute infarction.

Asunto(s)

Proteínas Adaptadoras Transductoras de Señales/genética , Daño por Reperfusión Miocárdica/genética , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Animales , Línea Celular , Modelos Animales de Enfermedad , Forminas , Regulación de la Expresión Génica , Humanos , Ratones , Daño por Reperfusión Miocárdica/fisiopatología , Miocardio/patología , Miocitos Cardíacos/patología , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/genética , Transducción de Señal/genética , Intercambiador de Sodio-Calcio/genética

RESUMEN

Histone deacetylase 3 (HDAC3), a chromatin-modifying enzyme, requires association with the deacetylase-containing domain (DAD) of the nuclear receptor corepressors NCOR1 and SMRT for its stability and activity. Here, we show that aldose reductase (AR), the rate-limiting enzyme of the polyol pathway, competes with HDAC3 to bind the NCOR1/SMRT DAD. Increased AR expression leads to HDAC3 degradation followed by increased PPARγ signaling, resulting in lipid accumulation in the heart. AR also downregulates expression of nuclear corepressor complex cofactors including Gps2 and Tblr1, thus affecting activity of the nuclear corepressor complex itself. Though AR reduces HDAC3-corepressor complex formation, it specifically derepresses the retinoic acid receptor (RAR), but not other nuclear receptors such as the thyroid receptor (TR) and liver X receptor (LXR). In summary, this work defines a distinct role for AR in lipid and retinoid metabolism through HDAC3 regulation and consequent derepression of PPARγ and RAR.

Asunto(s)

Aldehído Reductasa/metabolismo , PPAR gamma/metabolismo , Receptores de Ácido Retinoico/metabolismo , Animales , Células HEK293 , Histona Desacetilasas/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ratones , Co-Represor 1 de Receptor Nuclear/metabolismo , Unión Proteica

RESUMEN

BACKGROUND: Heart failure (HF) prognosis is negatively influenced by adverse environmental conditions associated with psychological distress and depression. The underlying mechanisms are not well understood because of insufficient experimental control in prior clinical and epidemiological studies. Using a validated animal model we examined whether distress-producing environmental manipulations (social isolation and crowding) increase HF progression following myocardial infarction (MI). METHODS: MI was induced using coronary artery ligation in 8-week old male Wistar rats (N=52) and results were compared to sham surgery (N=24). Housing conditions were randomly assigned at 5 days post MI or sham surgery (1/cage=isolation, 2/cage=standard reference condition, or 4/cage=crowding) and continued for 17 weeks until the end of observation. The open field test was used to test behavioral responses. Echocardiograms were obtained at weeks 8 and 16, and left ventricular (LV) weight at week 17. RESULTS: Housing conditions increased behavioral markers of distress (p=0.046) with the strongest effects for the isolated (1/cage) (p=0.022). MI did not increase distress-related behaviors compared to sham. MI-surgery resulted in characteristic HF indices (left ventricular ejection fraction (LVEF) at week 16=46 ± 12% vs. 80 ± 7% in sham, p<0.001). Housing condition was not related to LVEF or LV weight (p>0.10). CONCLUSIONS: Adverse environmental conditions, particularly isolated housing, produce increases in some of the behavioral indicators of distress. No effects of housing were found on post-MI progression of HF. The distress-HF associations observed in humans may therefore reflect common underlying factors rather than an independent causal pathway. Stronger environmental challenges may be needed in future animal research examining distress as related HF progression.

Asunto(s)

Aglomeración , Insuficiencia Cardíaca/fisiopatología , Infarto del Miocardio/fisiopatología , Aislamiento Social , Estrés Psicológico/fisiopatología , Animales , Aglomeración/psicología , Modelos Animales de Enfermedad , Ecocardiografía , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/psicología , Vivienda para Animales , Masculino , Infarto del Miocardio/complicaciones , Infarto del Miocardio/psicología , Distribución Aleatoria , Ratas Wistar , Aislamiento Social/psicología , Estrés Psicológico/complicaciones , Función Ventricular Izquierda/fisiología

RESUMEN

Oxidative stress is a central mechanism by which the receptor for advanced glycation endproducts (RAGE) mediates its pathological effects. Multiple experimental inquiries in RAGE-expressing cultured cells have demonstrated that ligand-RAGE interaction mediates generation of reactive oxygen species (ROS) and consequent downstream signal transduction and regulation of gene expression. The primary mechanism by which RAGE generates oxidative stress is via activation of NADPH oxidase; amplification mechanisms in the mitochondria may further drive ROS production. Recent studies indicating that the cytoplasmic domain of RAGE binds to the formin mDia1 provide further support for the critical roles of this pathway in oxidative stress; mDia1 was required for activation of rac1 and NADPH oxidase in primary murine aortic smooth muscle cells treated with RAGE ligand S100B. In vivo, in multiple distinct disease models in animals, RAGE action generates oxidative stress and modulates cellular/tissue fate in range of disorders, such as in myocardial ischemia, atherosclerosis, and aneurysm formation. Blockade or genetic deletion of RAGE was shown to be protective in these settings. Indeed, beyond cardiovascular disease, evidence is accruing in human subjects linking levels of RAGE ligands and soluble RAGE to oxidative stress in disorders such as doxorubicin toxicity, acetaminophen toxicity, neurodegeneration, hyperlipidemia, diabetes, preeclampsia, rheumatoid arthritis and pulmonary fibrosis. Blockade of RAGE signal transduction may be a key strategy for the prevention of the deleterious consequences of oxidative stress, particularly in chronic disease.

Asunto(s)

Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/patología , Productos Finales de Glicación Avanzada/metabolismo , Estrés Oxidativo/fisiología , Transducción de Señal/fisiología , Animales , Humanos

RESUMEN

We investigated the pre-clinical utility of carbon monoxide form of PEGylated hemoglobin (PEG-Hb also named SANGUINATE(™)) in myocardial infarction (MI) and in particular the response of diabetic tissues to superimposed ischemia/reperfusion injury. SANGUINATE(™) was evaluated in diabetic and normal mice subjected to 30 min of coronary artery ligation followed by either 48 h or 28 days of reperfusion. Our results demonstrate that SANGUINATE(™) was effective in reducing infarct size when administered either prior to left anterior descending coronary artery (LAD) occlusion or during reperfusion. This finding is an important step in exploring the efficacy of a pharmacoinvasive strategy using SANGUINATE(™) in patients with acute coronary syndromes.

Asunto(s)

Monóxido de Carbono/química , Monóxido de Carbono/farmacología , Complicaciones de la Diabetes/prevención & control , Corazón/efectos de los fármacos , Hemoglobinas/química , Hemoglobinas/farmacología , Daño por Reperfusión Miocárdica/prevención & control , Polietilenglicoles/química , Polietilenglicoles/farmacología , Animales , Biomarcadores/metabolismo , Sustitutos Sanguíneos/química , Sustitutos Sanguíneos/farmacología , Complicaciones de la Diabetes/metabolismo , Metabolismo Energético/efectos de los fármacos , Ratones , Infarto del Miocardio/complicaciones , Infarto del Miocardio/metabolismo , Infarto del Miocardio/prevención & control , Daño por Reperfusión Miocárdica/metabolismo , Estrés Oxidativo/efectos de los fármacos , Factores de Tiempo

RESUMEN

Mitochondrial dysfunction in heart failure includes greater susceptibility to mitochondrial permeability transition (MPT), which may worsen cardiac function and decrease survival. Treatment with a mixture of the n3 polyunsaturated fatty acids (n3 PUFAs) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) is beneficial in heart failure patients and increases resistance to MPT in animal models. We assessed whether DHA and EPA have similar effects when given individually, and whether 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 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 wk had impaired left ventricular function and increased cardiomyocyte apoptosis compared with normal hamsters, which was unaffected by n3 PUFA treatment. Evaluation of oxidative phosphorylation in isolated subsarcolemmal and interfibrillar mitochondria with substrates for complex I or II showed no effect of n3 PUFA treatment. On the other hand, interfibrillar mitochondria from cardiomyopathic hamsters were significantly more sensitive to Ca(2+)-induced MPT, which was completely normalized by treatment with DHA and partially 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. This suggest that greater susceptibility to MPT is not a contributor to cardiac pathology and poor survival in heart failure.

Asunto(s)

Cardiomiopatía Dilatada/tratamiento farmacológico , Cardiotónicos/farmacología , Ácidos Docosahexaenoicos/farmacología , Ácido Eicosapentaenoico/farmacología , Insuficiencia Cardíaca/tratamiento farmacológico , Mitocondrias Cardíacas/efectos de los fármacos , Proteínas de Transporte de Membrana Mitocondrial/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Animales , Animales Modificados Genéticamente , Apoptosis/efectos de los fármacos , Calcio/metabolismo , Cardiomiopatía Dilatada/genética , Cardiomiopatía Dilatada/metabolismo , Cardiomiopatía Dilatada/patología , Cardiomiopatía Dilatada/fisiopatología , Cricetinae , Modelos Animales de Enfermedad , Quimioterapia Combinada , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/fisiopatología , Masculino , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/patología , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Fosforilación Oxidativa/efectos de los fármacos , Fosfolípidos/metabolismo , Sarcoglicanos/deficiencia , Sarcoglicanos/genética , Volumen Sistólico/efectos de los fármacos , Factores de Tiempo , Función Ventricular Izquierda/efectos de los fármacos

RESUMEN

Insulin resistance is a characteristic feature of obesity and type 2 diabetes mellitus and impacts the heart in various ways. Impaired insulin-mediated glucose uptake is a uniformly observed characteristic of the heart in these states, although changes in upstream kinase signaling are variable and dependent on the severity and duration of the associated obesity or diabetes mellitus. The understanding of the physiological and pathophysiological role of insulin resistance in the heart is evolving. To maintain its high energy demands, the heart is capable of using many metabolic substrates. Although insulin signaling may directly regulate cardiac metabolism, its main role is likely the regulation of substrate delivery from the periphery to the heart. In addition to promoting glucose uptake, insulin regulates long-chain fatty acid uptake, protein synthesis, and vascular function in the normal cardiovascular system. Recent advances in understanding the role of metabolic, signaling, and inflammatory pathways in obesity have provided opportunities to better understand the pathophysiology of insulin resistance in the heart. This review will summarize our current understanding of metabolic mechanisms for and consequences of insulin resistance in the heart and will discuss potential new areas for investigating novel mechanisms that contribute to insulin resistance in the heart.

Asunto(s)

Complicaciones de la Diabetes/etiología , Diabetes Mellitus Tipo 2/complicaciones , Metabolismo Energético , Cardiopatías/etiología , Resistencia a la Insulina , Insulina/metabolismo , Miocardio/metabolismo , Obesidad/complicaciones , Animales , Glucemia/metabolismo , Complicaciones de la Diabetes/metabolismo , Complicaciones de la Diabetes/fisiopatología , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Ácidos Grasos/metabolismo , Cardiopatías/metabolismo , Cardiopatías/fisiopatología , Humanos , Obesidad/metabolismo , Obesidad/fisiopatología , Transducción de Señal

RESUMEN

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.

Asunto(s)

Ácido Araquidónico/metabolismo , Ácidos Docosahexaenoicos/metabolismo , Mitocondrias/metabolismo , Fosfolípidos/metabolismo , Animales , Calcio/metabolismo , Dieta , Suplementos Dietéticos , Masculino , Ratas , Ratas Wistar

RESUMEN

OBJECTIVE: 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. METHODS: 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). RESULTS: 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. CONCLUSION: A sugar-enriched diet did not exacerbate ventricular function, metabolic abnormalities, or survival in heart failure despite an increase in superoxide production.

Asunto(s)

Cardiomiopatías/fisiopatología , Sacarosa en la Dieta/administración & dosificación , Corazón/fisiopatología , Animales , Cardiomiopatías/genética , Cricetinae , Ecocardiografía , Ingestión de Energía , Fructosa/administración & dosificación , Glucosafosfato Deshidrogenasa/metabolismo , Glutatión/metabolismo , Corazón/efectos de los fármacos , Humanos , Peroxidación de Lípido , Lípidos/sangre , Masculino , NADP/metabolismo , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Sarcoglicanos/genética , Almidón/administración & dosificación

RESUMEN

AIMS: 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. METHODS AND RESULTS: 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. CONCLUSION: 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.

Asunto(s)

Grasas de la Dieta/administración & dosificación , Insuficiencia Cardíaca/dietoterapia , Animales , Animales Modificados Genéticamente , Cardiomiopatía Dilatada/dietoterapia , Cardiomiopatía Dilatada/genética , Cardiomiopatía Dilatada/metabolismo , Cardiomiopatía Dilatada/patología , Cricetinae , Dieta Alta en Grasa , Grasas Insaturadas en la Dieta/administración & dosificación , Ácidos Grasos/metabolismo , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/patología , Masculino , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/patología , Fosfolípidos/metabolismo , Sarcoglicanos/deficiencia , Sarcoglicanos/genética

RESUMEN

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.

Asunto(s)

Calcio/metabolismo , GTP Fosfohidrolasas/metabolismo , Proteínas de la Membrana/metabolismo , Mitocondrias/ultraestructura , Proteínas Mitocondriales/metabolismo , Miocitos Cardíacos/citología , Animales , Cardiomegalia/diagnóstico por imagen , Cardiomegalia/genética , Cardiomegalia/metabolismo , Muerte Celular , Células Cultivadas , GTP Fosfohidrolasas/genética , Eliminación de Gen , Corazón/fisiopatología , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Mitocondrias/patología , Proteínas Mitocondriales/genética , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/ultraestructura , Permeabilidad , Ratas , Especies Reactivas de Oxígeno/metabolismo , Ultrasonografía

RESUMEN

BACKGROUND: Pathological left ventricular (LV) hypertrophy frequently progresses to dilated heart failure with suppressed mitochondrial oxidative capacity. Dietary marine ω-3 polyunsaturated fatty acids (ω-3 PUFA) up-regulate adiponectin and prevent LV dilation in rats subjected to pressure overload. This study 1) assessed the effects of ω-3 PUFA on LV dilation and down-regulation of mitochondrial enzymes in response to pressure overload; and 2) evaluated the role of adiponectin in mediating the effects of ω-3 PUFA in heart. METHODS: Wild type (WT) and adiponectin-/- mice underwent transverse aortic constriction (TAC) and were fed standard chow ± ω-3 PUFA for 6 weeks. At 6 weeks, echocardiography was performed to assess LV function, mice were terminated, and mitochondrial enzyme activities were evaluated. RESULTS: TAC induced similar pathological LV hypertrophy compared to sham mice in both strains on both diets. In WT mice TAC increased LV systolic and diastolic volumes and reduced mitochondrial enzyme activities, which were attenuated by ω-3 PUFA without increasing adiponectin. In contrast, adiponectin-/- mice displayed no increase in LV end diastolic and systolic volumes or decrease in mitochondrial enzymes with TAC, and did not respond to ω-3 PUFA. CONCLUSION: These findings suggest ω-3 PUFA attenuates cardiac pathology in response to pressure overload independent of an elevation in adiponectin.

Asunto(s)

Adiponectina/sangre , Adiponectina/fisiología , Ácidos Grasos Omega-3/uso terapéutico , Hipertensión/fisiopatología , Hipertrofia Ventricular Izquierda/dietoterapia , Mitocondrias Cardíacas/enzimología , Adiponectina/genética , Animales , Biomarcadores/metabolismo , Ácidos Grasos/metabolismo , Proteínas Fetales/genética , Proteínas Fetales/metabolismo , Aceites de Pescado/química , Aceites de Pescado/uso terapéutico , Regulación de la Expresión Génica , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/prevención & control , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/metabolismo , Hipertrofia Ventricular Izquierda/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Miocardio/enzimología , Miocardio/metabolismo , Fosfolípidos/metabolismo , ARN Mensajero/metabolismo , Volumen Sistólico , Ultrasonografía

RESUMEN

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.

Asunto(s)

Calcio/farmacología , Cardiomegalia/metabolismo , Ácidos Docosahexaenoicos/farmacología , Ácido Eicosapentaenoico/farmacología , Mitocondrias Cardíacas/metabolismo , Animales , Ácido Araquidónico/metabolismo , Cardiomegalia/diagnóstico por imagen , Dieta , Suplementos Dietéticos , Ácidos Docosahexaenoicos/metabolismo , Ácido Eicosapentaenoico/metabolismo , Electrocardiografía , Ácidos Grasos/metabolismo , Masculino , Mitocondrias Cardíacas/efectos de los fármacos , Miocardio/metabolismo , Consumo de Oxígeno/efectos de los fármacos , Permeabilidad/efectos de los fármacos , Fosfolípidos/metabolismo , ARN Mensajero/biosíntesis , ARN Mensajero/aislamiento & purificación , Ratas , Ratas Wistar , Triglicéridos/metabolismo , Ultrasonografía

RESUMEN

Treatment with the omega-3 polyunsaturated fatty acids (PUFAs) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) exerts cardioprotective effects, and suppresses Ca2+-induced opening of the mitochondrial permeability transition pore (MPTP). These effects are associated with increased DHA and EPA, and lower arachidonic acid (ARA) in cardiac phospholipids. While clinical studies suggest the triglyceride lowering effects of DHA and EPA are equivalent, little is known about the independent effects of DHA and EPA on mitochondria function. We compared the effects of dietary supplementation with the omega-3 PUFAs DHA and EPA on cardiac mitochondrial phospholipid fatty acid composition and Ca2+-induced MPTP opening. Rats were fed a standard lab diet with either normal low levels of omega-3 PUFA, or DHA or EPA at 2.5% of energy intake for 8 weeks, and cardiac mitochondria were isolated and analyzed for Ca2+-induced MPTP opening and phospholipid fatty acyl composition. DHA supplementation increased both DHA and EPA and decreased ARA in mitochondrial phospholipid, and significantly delayed MPTP opening as assessed by increased Ca2+ retention capacity and decreased Ca2+-induced mitochondria swelling. EPA supplementation increased EPA in mitochondrial phospholipids, but did not affect DHA, only modestly lowered ARA, and did not affect MPTP opening. In summary, dietary supplementation with DHA but not EPA, profoundly altered mitochondrial phospholipid fatty acid composition and delayed Ca2+-induced MPTP opening.

Asunto(s)

Ácidos Docosahexaenoicos/administración & dosificación , Ácido Eicosapentaenoico/administración & dosificación , Ácidos Grasos/análisis , Mitocondrias Cardíacas/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/fisiología , Fosfolípidos/análisis , Animales , Calcio/metabolismo , Suplementos Dietéticos , Masculino , Mitocondrias Cardíacas/química , Poro de Transición de la Permeabilidad Mitocondrial , Consumo de Oxígeno , Ratas , Ratas Wistar

RESUMEN

Recent data suggest adiponectin, an adipocyte-derived hormone, affects development of heart failure in response to hypertension. Severe short-term pressure overload [1-3 wk of transverse aortic constriction (TAC)] in adiponectin(-/-) mice causes greater left ventricle (LV) hypertrophy than in wild-type (WT) mice, but conflicting results are reported regarding LV remodeling, with either increased or decreased LV end diastolic volume compared with WT mice. Here we assessed the effects of prolonged TAC on LV hypertrophy and remodeling. WT and adiponectin(-/-) mice were subjected to TAC and maintained for 6 wk. Regardless of strain, TAC induced similar LV hypertrophy ( approximately 70%) and upregulation of mRNA for heart failure marker genes. However, LV chamber size was dramatically different, with classic LV dilation in WT TAC mice but concentric LV hypertrophy in adiponectin(-/-) mice. LV end diastolic and systolic volumes were lower and ejection fraction higher in adiponectin(-/-) TAC mice compared with WT, indicating that adiponectin deletion prevented LV remodeling and deterioration in systolic function. The activities of marker enzymes of mitochondrial oxidative capacity were reduced in WT TAC mice by approximately 35%, whereas enzyme activities were maintained at sham levels in adiponectin(-/-) TAC mice. In conclusion, in WT mice, long-term pressure overload caused dilated LV hypertrophy accompanied by decreased activity of mitochondrial oxidative enzymes. Although adiponectin deletion did not affect LV hypertrophy, it prevented LV chamber remodeling and preserved mitochondrial oxidative capacity, suggesting that adiponectin plays a permissive role in mediating changes in cardiac structure and metabolism in response to pressure overload.

Asunto(s)

Insuficiencia Cardíaca Sistólica/fisiopatología , Hipertensión/fisiopatología , Hipertrofia Ventricular Izquierda/fisiopatología , Remodelación Ventricular/fisiología , Adiponectina/deficiencia , Adiponectina/fisiología , Animales , Presión Sanguínea/fisiología , Modelos Animales de Enfermedad , Insuficiencia Cardíaca Sistólica/etiología , Hipertensión/complicaciones , Hipertrofia Ventricular Izquierda/etiología , Masculino , Metaloproteasas , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias Cardíacas/enzimología , Contracción Miocárdica/fisiología

RESUMEN

Despite aggressive pharmacotherapy, heart failure is still clinical problem. Current therapies improve clinical symptoms and slow progression to heart failure, but overall the prognosis remains poor. Evidence from epidemiological, clinical and experimental studies indicates a beneficial role of the omega-3 polyunsaturated fatty acids (omega-3 PUFA) found in fish oils in the prevention and management of heart failure. Although the mechanisms is still unclear, clinical and animals studies indicate that the benefits of omega-3 PUFA may be attributed to a number of distinct biological effects on lipoprotein metabolism, inflammation response and mitochondrial function. This review summarise the data related to use of omega-3 PUFA supplementation as a potential treatment for heart failure and discussed possible mechanism of action.

Asunto(s)

Suplementos Dietéticos , Ácidos Grasos Omega-3/administración & dosificación , Aceites de Pescado/administración & dosificación , Insuficiencia Cardíaca/dietoterapia , Insuficiencia Cardíaca/metabolismo , Humanos , Lipoproteínas/metabolismo , Mitocondrias/metabolismo

RESUMEN

A high-fat diet can increase adiposity, leptin secretion, and plasma fatty acid concentration. In hypertension, this scenario may accelerate cardiac hypertrophy and development of heart failure but could be protective by activating peroxisome proliferator-activated receptors and expression of mitochondrial oxidative enzymes. We assessed the effects of a high-fat diet on the development of left ventricular hypertrophy, remodeling, contractile dysfunction, and the activity of mitochondrial oxidative enzymes. Mice (n = 10-12/group) underwent transverse aortic constriction (TAC) or sham surgery and were fed either a low-fat diet (10% of energy intake as fat) or a high-fat diet (45% fat) for 6 wk. The high-fat diet increased adipose tissue mass and plasma leptin and insulin. Left ventricular mass and chamber size were unaffected by diet in sham animals. TAC increased left ventricular mass (approximately 70%) and end-systolic and end-diastolic areas (approximately 100% and approximately 45%, respectively) to the same extent in both dietary groups. The high-fat diet increased plasma free fatty acid concentration and prevented the decline in the activity of the mitochondrial enzymes medium chain acyl-coenzyme A dehydrogenase (MCAD) and citrate synthase that was observed with TAC animals on a low-fat diet. In conclusion, a high-fat diet did not worsen cardiac hypertrophy or left ventricular chamber enlargement despite increases in fat mass and insulin and leptin concentrations. Furthermore, a high-fat diet preserved MCAD and citrate synthase activities during pressure overload, suggesting that it may help maintain mitochondrial oxidative capacity in failing myocardium.

Asunto(s)

Acil-CoA Deshidrogenasa/metabolismo , Adiposidad , Citrato (si)-Sintasa/metabolismo , Grasas de la Dieta/administración & dosificación , Insuficiencia Cardíaca/etiología , Hipertensión/enzimología , Hipertrofia Ventricular Izquierda/etiología , Mitocondrias Cardíacas/enzimología , Miocardio/enzimología , Acil-CoA Deshidrogenasa/genética , Animales , Biomarcadores/sangre , Glucemia/metabolismo , Proteína C-Reactiva/metabolismo , Citrato (si)-Sintasa/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Ácidos Grasos no Esterificados/sangre , Insuficiencia Cardíaca/enzimología , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/fisiopatología , Hipertensión/complicaciones , Hipertensión/patología , Hipertensión/fisiopatología , Hipertrofia Ventricular Izquierda/enzimología , Hipertrofia Ventricular Izquierda/patología , Hipertrofia Ventricular Izquierda/fisiopatología , Mediadores de Inflamación/sangre , Insulina/sangre , Interleucina-6/sangre , Leptina/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias Musculares/enzimología , Músculo Esquelético/enzimología , Contracción Miocárdica , Miocardio/patología , Oxidación-Reducción , ARN Mensajero/sangre , Factores de Tiempo , Triglicéridos/sangre , Factor de Necrosis Tumoral alfa/sangre , Remodelación Ventricular

RESUMEN

Consumption of omega-3 fatty acids from fish oil, specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), decreases risk for heart failure and attenuates pathologic cardiac remodeling in response to pressure overload. Dietary supplementation with EPA + DHA may also impact cardiac mitochondrial function and energetics through alteration of membrane phospholipids. We assessed the role of EPA + DHA supplementation on left ventricular (LV) function, cardiac mitochondrial membrane phospholipid composition, respiration, and sensitivity to mitochondrial permeability transition pore (MPTP) opening in normal and infarcted myocardium. Rats were subjected to sham surgery or myocardial infarction by coronary artery ligation (n=10-14), and fed a standard diet, or supplemented with EPA + DHA (2.3% of energy intake) for 12 weeks. EPA + DHA altered fatty acid composition of total mitochondrial phospholipids and cardiolipin by reducing arachidonic acid content and increasing DHA incorporation. EPA + DHA significantly increased calcium uptake capacity in both subsarcolemmal and intrafibrillar mitochondria from sham rats. This treatment effect persisted with the addition of cyclosporin A, and was not accompanied by changes in mitochondrial respiration or coupling, or cyclophilin D protein expression. Myocardial infarction resulted in heart failure as evidenced by LV dilation and contractile dysfunction. Infarcted LV myocardium had decreased mitochondrial protein yield and activity of mitochondrial marker enzymes, however respiratory function of isolated mitochondria was normal. EPA + DHA had no effect on LV function, mitochondrial respiration, or MPTP opening in rats with heart failure. In conclusion, dietary supplementation with EPA + DHA altered mitochondrial membrane phospholipid fatty acid composition in normal and infarcted hearts, but delayed MPTP opening only in normal hearts.

Asunto(s)

Calcio/farmacología , Grasas de la Dieta/farmacología , Ácidos Grasos Omega-3/farmacología , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Miocardio/metabolismo , Fosfolípidos/metabolismo , Animales , Peso Corporal/efectos de los fármacos , Cardiolipinas/metabolismo , Respiración de la Célula/efectos de los fármacos , Ciclosporina/farmacología , Ecocardiografía , Mitocondrias/efectos de los fármacos , Mitocondrias/enzimología , Poro de Transición de la Permeabilidad Mitocondrial , Miocardio/patología , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Superóxidos/metabolismo , Función Ventricular Izquierda/efectos de los fármacos