RESUMO
Cardiac dysfunction in obesity is associated with mitochondrial dysfunction, oxidative stress and altered insulin sensitivity. Whether oxidative stress directly contributes to myocardial insulin resistance remains to be determined. This study tested the hypothesis that ROS scavenging will improve mitochondrial function and insulin sensitivity in the hearts of rodent models with varying degrees of insulin resistance and hyperglycemia. The catalytic antioxidant MnTBAP was administered to the uncoupling protein-diphtheria toxin A (UCP-DTA) mouse model of insulin resistance (IR) and obesity, at early and late time points in the evolution of IR, and to db/db mice with severe obesity and type-two diabetes. Mitochondrial function was measured in saponin-permeabilized cardiac fibers. Aconitase activity and hydrogen peroxide emission were measured in isolated mitochondria. Insulin-stimulated glucose oxidation, glycolysis and fatty acid oxidation rates were measured in isolated working hearts, and 2-deoxyglucose uptake was measured in isolated cardiomyocytes. Four weeks of MnTBAP attenuated glucose intolerance in 13-week-old UCP-DTA mice but was without effect in 24-week-old UCP-DTA mice and in db/db mice. Despite the absence of improvement in the systemic metabolic milieu, MnTBAP reversed cardiac mitochondrial oxidative stress and improved mitochondrial bioenergetics by increasing ATP generation and reducing mitochondrial uncoupling in all models. MnTBAP also improved myocardial insulin mediated glucose metabolism in 13 and 24-week-old UCP-DTA mice. Pharmacological ROS scavenging improves myocardial energy metabolism and insulin responsiveness in obesity and type 2 diabetes via direct effects that might be independent of changes in systemic metabolism.
Assuntos
Antioxidantes/farmacologia , Síndrome Metabólica/tratamento farmacológico , Metaloporfirinas/farmacologia , Mitocôndrias Cardíacas/metabolismo , Animais , Antioxidantes/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Metabolismo Energético , Ácidos Graxos/metabolismo , Homeostase , Insulina/sangue , Resistência à Insulina , Síndrome Metabólica/sangue , Metaloporfirinas/uso terapêutico , Camundongos Endogâmicos C57BL , Camundongos Obesos , Miocárdio/metabolismo , Estresse Oxidativo , Transdução de SinaisRESUMO
Phosphoinositide-dependent protein kinase-1 (PDPK1) is an important mediator of phosphatidylinositol 3-kinase (PI3K) signaling. We previously reported that PI3K but not Akt signaling mediates the increase in mitochondrial oxidative capacity following physiological cardiac hypertrophy. To determine if PDPK1 regulates these metabolic adaptations we examined mice with cardiomyocyte-specific heterozygous knockout of PDPK1 (cPDPK1(+/-)) after 5 wk. exercise swim training. Akt phosphorylation at Thr308 increased by 43% in wildtype (WT) mice but not in cPDPK1(+/-) mice following exercise training. Ventricular contractile function was not different between WT and cPDPK1(+/-) mice at baseline. In addition, exercise did not influence ventricular function in WT or cPDPK1(+/-) mice. Heart weight normalized to tibia length ratios increased by 13.8% in WT mice (6.2±0.2 vs. 7.1±0.2, P=0.001), but not in cPDPK1(+/-) (6.2±0.3 vs. 6.5±0.2, P=0.20) mice after swim training. Diastolic LV dimension increased in WT mice (3.7±0.1 vs. 4.0±0.1 mm, P=0.01) but not in cPDPK1(+/-) (3.8±0.1 vs. 3.7±0.1 mm, P=0.56) following swim training. Maximal mitochondrial oxygen consumption (VADP, nmol/min/mg) using palmitoyl carnitine as a substrate was significantly increased in mice of all genotypes following swim training (WT: 13.6±0.6 vs.16.1±0.9, P=0.04; cPDPK1(+/-): 12.4±0.6 vs.15.9±1.2, P=0.04). These findings suggest that PDPK1 is required for exercise-induced cardiac hypertrophy but does not contribute to exercise-induced increases in mitochondrial function.
Assuntos
Proteínas Quinases Dependentes de 3-Fosfoinositídeo/metabolismo , Adaptação Fisiológica , Cardiomegalia/enzimologia , Cardiomegalia/patologia , Mitocôndrias Cardíacas/metabolismo , Condicionamento Físico Animal , Animais , Cateterismo Cardíaco , Cardiomegalia/complicações , Cardiomegalia/fisiopatologia , Deleção de Genes , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Homozigoto , Insulina/farmacologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias Cardíacas/efeitos dos fármacos , Modelos Biológicos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Fosfotreonina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ultrassonografia , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
During pathological hypertrophy, peroxisome proliferator-activated receptor coactivator 1α (PGC-1α) is repressed in concert with reduced mitochondrial oxidative capacity and fatty acid oxidation (FAO). We therefore sought to determine if maintaining or increasing PGC-1α levels in the context of pressure overload hypertrophy (POH) would preserve mitochondrial function and prevent contractile dysfunction. Pathological cardiac hypertrophy was induced using 4 wk of transverse aortic constriction (TAC) in mice overexpressing the human PGC-1α genomic locus via a bacterial artificial chromosome (TG) and nontransgenic controls (Cont). PGC-1α levels were increased by 40% in TG mice and were sustained following TAC. Although TAC-induced repression of FAO genes and oxidative phosphorylation (oxphos) genes was prevented in TG mice, mitochondrial function and ATP synthesis were equivalently impaired in Cont and TG mice after TAC. Contractile function was also equally impaired in Cont and TG mice following TAC, as demonstrated by decreased +dP/dt and ejection fraction and increased left ventricular developed pressure and end diastolic pressure. Conversely, capillary density was preserved, in concert with increased VEGF expression, while apoptosis and fibrosis were reduced in TG relative to Cont mice after TAC. Hence, sustaining physiological levels of PGC-1α expression following POH, while preserving myocardial vascularity, does not prevent mitochondrial and contractile dysfunction.
Assuntos
Cardiomegalia/fisiopatologia , Neovascularização Fisiológica/fisiologia , Fatores de Transcrição/fisiologia , Trifosfato de Adenosina/biossíntese , Animais , Aorta , Apoptose , Capilares/ultraestrutura , Cardiomegalia/etiologia , Constrição , Fibrose , Humanos , Hipertensão/complicações , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Transgênicos , Mitocôndrias Cardíacas/fisiologia , Contração Miocárdica/fisiologia , Oxirredução , Fosforilação Oxidativa , Palmitatos/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , RNA Mensageiro/biossíntese , Proteínas Recombinantes/metabolismo , Volume Sistólico , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética , Fator A de Crescimento do Endotélio Vascular/biossíntese , Fator A de Crescimento do Endotélio Vascular/genética , Remodelação VentricularRESUMO
The aim of this study was to determine whether endogenous GLUT1 induction and the increased glucose utilization that accompanies pressure overload hypertrophy (POH) are required to maintain cardiac function during hemodynamic stress, and to test the hypothesis that lack of GLUT1 will accelerate the transition to heart failure. To determine the contribution of endogenous GLUT1 to the cardiac adaptation to POH, male mice with cardiomyocyte-restricted deletion of the GLUT1 gene (G1KO) and their littermate controls (Cont) were subjected to transverse aortic constriction (TAC). GLUT1 deficiency reduced glycolysis and glucose oxidation by 50%, which was associated with a reciprocal increase in fatty acid oxidation (FAO) relative to controls. Four weeks after TAC, glycolysis increased and FAO decreased by 50% in controls, but were unchanged in G1KO hearts relative to shams. G1KO and controls exhibited equivalent degrees of cardiac hypertrophy, fibrosis, and capillary density loss after TAC. Following TAC, in vivo left ventricular developed pressure was decreased in G1KO hearts relative to controls, but+dP/dt was equivalently reduced in Cont and G1KO mice. Mitochondrial function was equivalently impaired following TAC in both Cont and G1KO hearts. GLUT1 deficiency in cardiomyocytes alters myocardial substrate utilization, but does not substantially exacerbate pressure-overload induced contractile dysfunction or accelerate the progression to heart failure.
Assuntos
Transportador de Glucose Tipo 1/deficiência , Insuficiência Cardíaca/fisiopatologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Mitocôndrias Cardíacas/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Animais , Transporte Biológico , Débito Cardíaco , Expressão Gênica , Glucose/metabolismo , Transportador de Glucose Tipo 1/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Contração Miocárdica , Miocárdio/metabolismo , Miócitos Cardíacos/patologia , Técnicas de Cultura de Órgãos , Consumo de Oxigênio , Cultura Primária de CélulasRESUMO
RATIONALE: Pressure overload cardiac hypertrophy, a risk factor for heart failure, is associated with reduced mitochondrial fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) proteins that correlate in rodents with reduced PGC-1α expression. OBJECTIVE: To determine the role of PGC-1ß in maintaining mitochondrial energy metabolism and contractile function in pressure overload hypertrophy. METHODS AND RESULTS: PGC-1ß deficient (KO) mice and wildtype (WT) controls were subjected to transverse aortic constriction (TAC). Although LV function was modestly reduced in young KO hearts, there was no further decline with age so that LV function was similar between KO and WT when TAC was performed. WT-TAC mice developed relatively compensated LVH, despite reduced mitochondrial function and repression of OXPHOS and FAO genes. In nonstressed KO hearts, OXPHOS gene expression and palmitoyl-carnitine-supported mitochondrial function were reduced to the same extent as banded WT, but FAO gene expression was normal. Following TAC, KO mice progressed more rapidly to heart failure and developed more severe mitochondrial dysfunction, despite a similar overall pattern of repression of OXPHOS and FAO genes as WT-TAC. However, in relation to WT-TAC, PGC-1ß deficient mice exhibited greater degrees of oxidative stress, decreased cardiac efficiency, lower rates of glucose metabolism, and repression of hexokinase II protein. CONCLUSIONS: PGC-1ß plays an important role in maintaining baseline mitochondrial function and cardiac contractile function following pressure overload hypertrophy by preserving glucose metabolism and preventing oxidative stress.
Assuntos
Pressão Sanguínea , Metabolismo Energético , Insuficiência Cardíaca/etiologia , Hipertrofia Ventricular Esquerda/complicações , Mitocôndrias Cardíacas/metabolismo , Miocárdio/metabolismo , Transativadores/deficiência , Disfunção Ventricular Esquerda/etiologia , Envelhecimento , Animais , Modelos Animais de Doenças , Progressão da Doença , Metabolismo Energético/genética , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica , Glucose/metabolismo , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/prevenção & controle , Hexoquinase/metabolismo , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/fisiopatologia , Camundongos , Camundongos Knockout , Contração Miocárdica , Oxirredução , Fosforilação Oxidativa , Estresse Oxidativo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Transativadores/genética , Fatores de Transcrição , Ultrassonografia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/prevenção & controle , Função Ventricular EsquerdaRESUMO
Nitroalkene derivatives of nitro-oleic acid (OA-NO2) are endogenous lipid products with potent anti-inflammatory properties in vitro. The present study was undertaken to evaluate the in vivo anti-inflammatory effect of OA-NO2 in mice given LPS. Two days before LPS administration, C57BL/6J mice were chronically infused with vehicle (LPS vehicle) or OA-NO2 (LPS OA-NO2) at 200 microg x kg(-1) x day(-1) via osmotic minipumps; LPS was administered via a single intraperitoneal (ip) injection (10 mg/kg in saline). A third group received an ip injection of saline without LPS or OA-NO2 and served as controls. At 18 h of LPS administration, LPS vehicle mice displayed multiorgan dysfunction as evidenced by elevated plasma urea and creatinine (kidney), aspartate aminotransferase (AST) and alanine aminotransferase (ALT; liver), and lactate dehydrogenase (LDH) and reduced ejection fraction (heart). In contrast, the severity of multiorgan dysfunction was less in LPS OA-NO2 animals. The levels of circulating TNF-alpha and renal TNF-alpha mRNA expression, together with renal mRNA expression of monocyte chemoattractant protein-1, ICAM-1, and VCAM-1, and with renal mRNA and protein expression of inducible nitric oxide synthase and cyclooxygenase 2, and renal cGMP and PGE2 contents, were greater in LPS vehicle vs. control mice, but were attenuated in LPS OA-NO2 animals. Similar patterns of changes in the expression of inflammatory mediators were observed in the liver. Together, pretreatment with OA-NO2 ameliorated the inflammatory response and multiorgan injury in endotoxin-induced endotoxemia in mice.
Assuntos
Anti-Inflamatórios/administração & dosagem , Endotoxemia/tratamento farmacológico , Cardiopatias/prevenção & controle , Mediadores da Inflamação/metabolismo , Nefropatias/prevenção & controle , Hepatopatias/prevenção & controle , Ácidos Oleicos/administração & dosagem , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Nitrogênio da Ureia Sanguínea , Temperatura Corporal/efeitos dos fármacos , Moléculas de Adesão Celular/sangue , Quimiocinas/sangue , Creatinina/sangue , GMP Cíclico/metabolismo , Ciclo-Oxigenase 2/metabolismo , Citocinas/sangue , Dinoprostona/metabolismo , Modelos Animais de Doenças , Esquema de Medicação , Endotoxemia/induzido quimicamente , Endotoxemia/imunologia , Endotoxemia/fisiopatologia , Cardiopatias/imunologia , Cardiopatias/metabolismo , Cardiopatias/fisiopatologia , Hematócrito , Mediadores da Inflamação/sangue , Bombas de Infusão Implantáveis , Rim/efeitos dos fármacos , Rim/imunologia , Rim/metabolismo , Nefropatias/imunologia , Nefropatias/metabolismo , Nefropatias/fisiopatologia , Lipopolissacarídeos , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/metabolismo , Hepatopatias/imunologia , Hepatopatias/metabolismo , Hepatopatias/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/imunologia , Miocárdio/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Volume Sistólico/efeitos dos fármacos , Fatores de TempoRESUMO
Cardiac glucose uptake and oxidation are reduced in diabetes despite hyperglycemia. Mitochondrial dysfunction contributes to heart failure in diabetes. It is unclear whether these changes are adaptive or maladaptive. To directly evaluate the relationship between glucose delivery and mitochondrial dysfunction in diabetic cardiomyopathy, we generated transgenic mice with inducible cardiomyocyte-specific expression of the GLUT4. We examined mice rendered hyperglycemic following low-dose streptozotocin prior to increasing cardiomyocyte glucose uptake by transgene induction. Enhanced myocardial glucose in nondiabetic mice decreased mitochondrial ATP generation and was associated with echocardiographic evidence of diastolic dysfunction. Increasing myocardial glucose delivery after short-term diabetes onset exacerbated mitochondrial oxidative dysfunction. Transcriptomic analysis revealed that the largest changes, driven by glucose and diabetes, were in genes involved in mitochondrial function. This glucose-dependent transcriptional repression was in part mediated by O-GlcNAcylation of the transcription factor Sp1. Increased glucose uptake induced direct O-GlcNAcylation of many electron transport chain subunits and other mitochondrial proteins. These findings identify mitochondria as a major target of glucotoxicity. They also suggest that reduced glucose utilization in diabetic cardiomyopathy might defend against glucotoxicity and caution that restoring glucose delivery to the heart in the context of diabetes could accelerate mitochondrial dysfunction by disrupting protective metabolic adaptations.
Assuntos
Diabetes Mellitus , Cardiomiopatias Diabéticas , Animais , Cardiomiopatias Diabéticas/genética , Ácidos Graxos , Glucose , Camundongos , Mitocôndrias , MiocárdioRESUMO
Diabetes increases mortality and accelerates left ventricular (LV) dysfunction following myocardial infarction (MI). This study sought to determine the impact of impaired myocardial insulin signaling, in the absence of diabetes, on the development of LV dysfunction following MI. Mice with cardiomyocyte-restricted knock out of the insulin receptor (CIRKO) and wildtype (WT) mice were subjected to proximal left coronary artery ligation (MI) and followed for 14 days. Despite equivalent infarct size, mortality was increased in CIRKO-MI vs. WT-MI mice (68% vs. 40%, respectively). In surviving mice, LV ejection fraction and dP/dt were reduced by >40% in CIRKO-MI vs. WT-MI. Relative to shams, isometric developed tension in LV papillary muscles increased in WT-MI but not in CIRKO-MI. Time to peak tension and relaxation times were prolonged in CIRKO-MI vs. WT-MI suggesting impaired, load-independent myocardial contractile function. To elucidate mechanisms for impaired LV contractility, mitochondrial function was examined in permeabilized cardiac fibers. Whereas maximal ADP-stimulated mitochondrial O(2) consumption rates (V(ADP)) with palmitoyl carnitine were unchanged in WT-MI mice relative to sham-operated animals, V(ADP) was significantly reduced in CIRKO-MI (13.17+/-0.94 vs. 9.14+/-0.88 nmol O(2)/min/mgdw, p<0.05). Relative to WT-MI, expression levels of GLUT4, PPAR-alpha, SERCA2, and the FA-Oxidation genes MCAD, LCAD, CPT2 and the electron transfer flavoprotein ETFDH were repressed in CIRKO-MI. Thus reduced insulin action in cardiac myocytes accelerates post-MI LV dysfunction, due in part to a rapid decline in mitochondrial FA oxidative capacity, which combined with limited glucose transport capacity that may reduce substrate utilization and availability.
Assuntos
Mitocôndrias Cardíacas/metabolismo , Receptor de Insulina/fisiologia , Acil-CoA Desidrogenase/metabolismo , Acil-CoA Desidrogenase de Cadeia Longa/metabolismo , Animais , Ecocardiografia , Ácidos Graxos/metabolismo , Feminino , Transportador de Glucose Tipo 4/metabolismo , Metabolismo dos Lipídeos/genética , Camundongos , Camundongos Knockout , Mitocôndrias Cardíacas/patologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Consumo de Oxigênio , PPAR alfa/metabolismo , Reação em Cadeia da Polimerase , Receptor de Insulina/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/fisiologiaRESUMO
Measured monthly atmospheric depositional fluxes of cosmogenically produced (7)Be ranged from 1 to 67 mBq/cm(2) in Boston, Massachusetts between September 2000 and August 2007. These fluxes exhibited seasonality and supported a decay-corrected (7)Be atmospheric depositional running inventory that ranged from 36 to 144 mBq/cm(2). Annual (7)Be deposition exhibited an increasing trend that may reflect a general decrease in solar activity and a general increase in precipitation over the 7-year sampling period. To investigate short-term sediment dynamics and accumulation patterns in the Neponset River estuary, we collected six sediment cores in July 2006 and measured (7)Be sediment inventories ranging from 48 to 546 mBq/cm(2) Comparisons of these sediment inventories with the (7)Be running inventory from atmospheric deposition (101 mBq/cm(2)) at the time of core collection indicated a large degree of spatial heterogeneity in sediment accumulation patterns and its potential use as a tool for assessing the impacts of environmental restoration activities in estuarine environments.
Assuntos
Poluentes Radioativos do Ar/análise , Berílio/análise , Radioisótopos/análise , Poluentes Radioativos da Água/análise , Monitoramento Ambiental , Geografia , Massachusetts , RiosRESUMO
Considerable efforts have been made to exploit cardioprotective drugs and gene delivery systems for myocardial infarction (MI). The promising cardioprotective effects of recombinant human erythropoietin (rHuEPO) protein in animal experiments have not been consistently reproduced in clinical human trials of acute MI; however, the mechanisms underlying the inconsistent discrepancies are not yet fully understood. We hypothesized that the plasmid human erythropoietin gene (phEPO) delivered by our bioreducible polymer might produce cardioprotective effects on post-infarct cardiac remodeling. We demonstrated that intramyocardial delivery of phEPO by an arginine-grafted poly(disulfide amine) (ABP) polymer in infarcted rats preserves cardiac geometry and systolic function. The reduced infarct size of phEPO/ABP delivery was followed by decrease in fibrosis, protection from cardiomyocyte loss, and down-regulation of apoptotic activity. In addition, the increased angiogenesis and decreased myofibroblast density in the border zone of the infarct support the beneficial effects of phEPO/ABP administration. Furthermore, phEPO/ABP delivery induced prominent suppression on Ang II and TGF-ß activity in all subdivisions of cardiac tissues except for the central zone of infarct. These results of phEPO gene therapy delivered by a bioreducible ABP polymer provide insight into the lack of phEPO gene therapy translation in the treatment of acute MI to human trials.
Assuntos
Arginina/administração & dosagem , Cardiotônicos/administração & dosagem , Eritropoetina/genética , Infarto do Miocárdio/terapia , Poliaminas/administração & dosagem , Animais , Arginina/química , Cardiotônicos/química , Eritropoetina/química , Técnicas de Transferência de Genes , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Poliaminas/química , Ratos , Ratos Sprague-Dawley , Remodelação VentricularRESUMO
BACKGROUND: Increased glucose transporter 1 (GLUT1) expression and glucose utilization that accompany pressure overload-induced hypertrophy (POH) are believed to be cardioprotective. Moreover, it has been shown that lifelong transgenic overexpression of GLUT1 in the heart prevents cardiac dysfunction after aortic constriction. The relevance of this model to clinical practice is unclear because of the life-long duration of increased glucose metabolism. Therefore, we sought to determine if a short-term increase in GLUT1-mediated myocardial glucose uptake would still confer cardioprotection if overexpression occurred at the onset of POH. METHODS AND RESULTS: Mice with cardiomyocyte-specific inducible overexpression of a hemagglutinin (HA)-tagged GLUT1 transgene (G1HA) and their controls (Cont) were subjected to transverse aortic constriction (TAC) 2 days after transgene induction with doxycycline (DOX). Analysis was performed 4 weeks after TAC. Mitochondrial function, adenosine triphosphate (ATP) synthesis, and mRNA expression of oxidative phosphorylation (OXPHOS) genes were reduced in Cont mice, but were maintained in concert with increased glucose utilization in G1HA following TAC. Despite attenuated adverse remodeling in G1HA relative to control TAC mice, cardiac hypertrophy was exacerbated in these mice, and positive dP/dt (in vivo) and cardiac power (ex vivo) were equivalently decreased in Cont and G1HA TAC mice compared to shams, consistent with left ventricular dysfunction. O-GlcNAcylation of Ca2+ cycling proteins was increased in G1HA TAC hearts. CONCLUSIONS: Short-term cardiac specific induction of GLUT1 at the onset of POH preserves mitochondrial function and attenuates pathological remodeling, but exacerbates the hypertrophic phenotype and is insufficient to prevent POH-induced cardiac contractile dysfunction, possibly due to impaired calcium cycling.
Assuntos
Transportador de Glucose Tipo 1/biossíntese , Mitocôndrias/fisiologia , Disfunção Ventricular Esquerda/metabolismo , Remodelação Ventricular/fisiologia , Animais , Masculino , Camundongos , Camundongos Transgênicos , Óxido Nítrico Sintase Tipo II , PressãoRESUMO
Mechanistic target of rapamycin (Mtor) is required for embryonic inner cell mass proliferation during early development. However, Mtor expression levels are very low in the mouse heart during embryogenesis. To determine if Mtor plays a role during mouse cardiac development, cardiomyocyte specific Mtor deletion was achieved using α myosin heavy chain (α-MHC) driven Cre recombinase. Initial mosaic expression of Cre between embryonic day (E) 10.5 and E11.5 eliminated a subset of cardiomyocytes with high Cre activity by apoptosis and reduced overall cardiac proliferative capacity. The remaining cardiomyocytes proliferated and expanded normally. However loss of 50% of cardiomyocytes defined a threshold that impairs the ability of the embryonic heart to sustain the embryo's circulatory requirements. As a result 92% of embryos with cardiomyocyte Mtor deficiency died by the end of gestation. Thus Mtor is required for survival and proliferation of cardiomyocytes in the developing heart.
Assuntos
Desenvolvimento Embrionário/fisiologia , Coração/embriologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Western Blotting , Desenvolvimento Embrionário/genética , Feminino , Camundongos , Camundongos Knockout , Serina-Treonina Quinases TOR/genéticaRESUMO
These studies investigate the role of uncoupling protein 3 (UCP3) in cardiac energy metabolism, cardiac O(2) consumption (MVO(2)), cardiac efficiency (CE), and mitochondrial uncoupling in high fat (HF)-fed or leptin-deficient mice. UCP3KO and wild-type (WT) mice were fed normal chow or HF diets for 10 weeks. Substrate utilization rates, MVO(2), CE, and mitochondrial uncoupling were measured in perfused working hearts and saponin-permeabilized cardiac fibers, respectively. Similar analyses were performed in hearts of ob/ob mice lacking UCP3 (U3OB mice). HF increased cardiac UCP3 protein. However, fatty acid (FA) oxidation rates were similarly increased by HF diet in WT and UCP3KO mice. By contrast, MVO(2) increased in WT, but not in UCP3KO with HF, leading to increased CE in UCP3KO mice. Consistent with increased CE, mitochondrial coupling was increased in the hearts of HF-fed UCP3KO mice. Unexpectedly, UCP3 deletion in ob/ob mice reduced FA oxidation but had no effect on MVO(2) or CE. In addition, FA-induced mitochondrial uncoupling was similarly enhanced in U3OB compared with ob/ob hearts and was associated with elevated mitochondrial thioesterase-1 protein content. These studies show that although UCP3 may mediate mitochondrial uncoupling and reduced CE after HF feeding, it does not mediate uncoupling in leptin-deficient states.
Assuntos
Metabolismo Energético/fisiologia , Canais Iônicos/metabolismo , Leptina/deficiência , Proteínas Mitocondriais/metabolismo , Consumo de Oxigênio/fisiologia , Animais , Gorduras na Dieta/efeitos adversos , Metabolismo Energético/genética , Canais Iônicos/genética , Leptina/genética , Masculino , Camundongos , Camundongos Knockout , Mitocôndrias , Proteínas Mitocondriais/genética , Consumo de Oxigênio/genética , Palmitoil-CoA Hidrolase/metabolismo , Proteína Desacopladora 3RESUMO
Triclosan is an antimicrobial agent added to a wide array of consumer goods and personal care products. Through its use, it is introduced into municipal sewer systems where it is only partially removed during wastewater treatment. In this study, triclosan was measured in dated sediment cores from four urbanized estuaries in order to reconstruct temporal and spatial trends of accumulation. Measurable concentrations of triclosan first appeared in each of the sediment cores near 1964, which corresponds with the US patent issuance date of triclosan. The presence of triclosan at each of the study sites at or near the patent date indicates that long-term preservation is occurring in estuarine sediments. Temporal trends of triclosan at each location are unique, reflecting between site variability. Concentrations at one site climbed to as high as 400ngg(-1), due in part, to local commercial production of triclosan. At two locations, levels of triclosan rise towards the surface of each core, suggesting increasing usage in recent years. One location adjacent to a major combined sewer overflow had high sediment concentrations of triclosan, confirming their potential as a source of triclosan to estuaries.
Assuntos
Sedimentos Geológicos/química , Triclosan/toxicidade , Movimentos da Água , Poluentes Químicos da Água , Técnicas de Laboratório Clínico , Monitoramento Ambiental , Humanos , Inseticidas , Eliminação de Resíduos , Poluentes do Solo , Fatores de Tempo , Distribuição Tecidual , Urbanização , Eliminação de Resíduos LíquidosRESUMO
Bradykinin signaling has been proposed to play either protective or deleterious roles in the development of cardiac dysfunction in response to various pathological stimuli. To further define the role of bradykinin signaling in the diabetic heart, we examined cardiac function in mice with genetic ablation of both bradykinin B1 and B2 receptors (B1RB2R(-/-)) in the context of the Akita model of insulin-deficient type 1 diabetes (Ins2(Akita/+)). In 5-month-old diabetic and nondiabetic, wild-type and B1RB2R(-/-) mice, in vivo cardiac contractile function was determined by left-ventricular (LV) catheterization and echocardiography. Reactive oxygen species levels were measured by 2'-7'-dichlorofluorescein diacetate fluorescence. Mitochondrial function and ATP synthesis were determined in saponin-permeabilized cardiac fibers. LV systolic pressure and the peak rate of LV pressure rise and decline were decreased with diabetes but did not deteriorate further with loss of bradykinin signaling. Wall thinning and reduced ejection fractions in Akita mouse hearts were partially attenuated by B1RB2R deficiency, although other parameters of LV function were unaffected. Loss of bradykinin signaling did not increase fibrosis in Ins2(Akita/+) diabetic mouse hearts. Mitochondrial dysfunction was not exacerbated by B1RB2R deficiency, nor was there any additional increase in tissue levels of reactive oxygen species. Thus, loss of bradykinin B2 receptor signaling does not abrogate the previously reported beneficial effect of inhibition of B1 receptor signaling. In conclusion, complete loss of bradykinin expression does not worsen cardiac function or increase myocardial fibrosis in diabetes.
Assuntos
Bradicinina/fisiologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Cardiopatias/etiologia , Animais , Bradicinina/metabolismo , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/fisiopatologia , Feminino , Coração/fisiopatologia , Cardiopatias/genética , Cardiopatias/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias Cardíacas/patologia , Mitocôndrias Cardíacas/fisiologia , Miocárdio/patologia , Estresse Oxidativo/genética , Receptor B1 da Bradicinina/deficiência , Receptor B1 da Bradicinina/genética , Receptor B2 da Bradicinina/deficiência , Receptor B2 da Bradicinina/genética , Transdução de Sinais/genética , Fatores de TempoRESUMO
The distribution of Triclosan within the Hudson River Estuary can be explained by a balance among the overall effluent inputs from municipal sewage treatment facilities, dilution of Triclosan concentrations in the water column with freshwater and seawater inputs, removal of Triclosan from the water column by adsorption to particles, and loss to photodegradation. This study shows that an average water column concentration of 3+/-2 ng/l (in the lower Hudson River Estuary) is consistent with an estimate for dilution of average wastewater concentrations with seawater and calculated rates of adsorption of Triclosan to particles. An average Triclosan sediment concentration of 26+/-11 ng/g would be in equilibrium with the overlying water column if Triclosan has a particle-to-water partitioning coefficient of k(d) approximately 10(4), consistent with laboratory estimates.
Assuntos
Sedimentos Geológicos/química , Rios/química , Triclosan/análise , Poluentes Químicos da Água/análise , Anti-Infecciosos Locais/análise , Monitoramento AmbientalRESUMO
The short-lived, fission-produced radioisotope, 131I (t1/2 = 8.04 days), was detected in wastewater, surficial sediment, and suspended particulate matter (SPM) samples collected from New York Harbor (NYH) between 2001 and 2002. lodine-131 is used as a radiopharmaceutical for medical imaging, diagnostics, and treatments for conditions of the thyroid. It is introduced into the municipal waste stream by medical facilities and patients and is subsequently released into the estuary via wastewater effluent. Measured 131I activities in surface sediments were correlated with those of 7Be (t1/2 = 53.2 days), a naturally occurring radioisotope that is widely used to quantify particle dynamics, sediment focusing, and short-term sediment deposition and accumulation in aquatic systems. Surficial sediment 131I activities were also compared with measured trace metal (Cu, Pb) and organic carbon (OC(sed)) concentrations which can be linked to wastewater inputs. These preliminary results from NYH introduce 131I as a potentially valuable source-specific, shortlived biogeochemical tracer (timescales < 1 month) for particles, sediments, and wastewater-sourced contaminants in urbanized aquatic systems.