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1.
Pflugers Arch ; 473(3): 461-475, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33454842

RESUMO

Atrial fibrillation (AF) is strongly associated with risk of stroke and heart failure. AF promotes atrial remodeling that increases risk of stroke due to left atrial thrombogenesis, and increases energy demand to support high rate electrical activity and muscle contraction. While many transcriptomic studies have assessed AF-related changes in mRNA abundance, fewer studies have assessed proteomic changes. We performed a proteomic analysis on left atrial appendage (LAA) tissues from 12 patients with a history of AF undergoing elective surgery; atrial rhythm was documented at time of surgery. Proteomic analysis was performed using liquid chromatography with mass spectrometry (LC/MS-MS). Data-dependent analysis identified 3090 unique proteins, with 408 differentially expressed between sinus rhythm and AF. Ingenuity Pathway Analysis of differentially expressed proteins identified mitochondrial dysfunction, oxidative phosphorylation, and sirtuin signaling among the most affected pathways. Increased abundance of electron transport chain (ETC) proteins in AF was accompanied by decreased expression of ETC complex assembly factors, tricarboxylic acid cycle proteins, and other key metabolic modulators. Discordant changes were also evident in the contractile unit with both up and downregulation of key components. Similar pathways were affected in a comparison of patients with a history of persistent vs. paroxysmal AF, presenting for surgery in sinus rhythm. Together, these data suggest that while the LAA attempts to meet the energetic demands of AF, an uncoordinated response may reduce ATP availability, contribute to tissue contractile and electrophysiologic heterogeneity, and promote a progression of AF from paroxysmal episodes to development of a substrate amenable to persistent arrhythmia.


Assuntos
Apêndice Atrial/metabolismo , Fibrilação Atrial/metabolismo , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteômica
3.
J Physiol ; 594(24): 7341-7360, 2016 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-27558544

RESUMO

KEY POINTS: Hyperammonaemia occurs in hepatic, cardiac and pulmonary diseases with increased muscle concentration of ammonia. We found that ammonia results in reduced skeletal muscle mitochondrial respiration, electron transport chain complex I dysfunction, as well as lower NAD+ /NADH ratio and ATP content. During hyperammonaemia, leak of electrons from complex III results in oxidative modification of proteins and lipids. Tricarboxylic acid cycle intermediates are decreased during hyperammonaemia, and providing a cell-permeable ester of αKG reversed the lower TCA cycle intermediate concentrations and increased ATP content. Our observations have high clinical relevance given the potential for novel approaches to reverse skeletal muscle ammonia toxicity by targeting the TCA cycle intermediates and mitochondrial ROS. ABSTRACT: Ammonia is a cytotoxic metabolite that is removed primarily by hepatic ureagenesis in humans. Hyperammonaemia occurs in advanced hepatic, cardiac and pulmonary disease, and in urea cycle enzyme deficiencies. Increased skeletal muscle ammonia uptake and metabolism are the major mechanism of non-hepatic ammonia disposal. Non-hepatic ammonia disposal occurs in the mitochondria via glutamate synthesis from α-ketoglutarate resulting in cataplerosis. We show skeletal muscle mitochondrial dysfunction during hyperammonaemia in a comprehensive array of human, rodent and cellular models. ATP synthesis, oxygen consumption, generation of reactive oxygen species with oxidative stress, and tricarboxylic acid (TCA) cycle intermediates were quantified. ATP content was lower in the skeletal muscle from cirrhotic patients, hyperammonaemic portacaval anastomosis rat, and C2C12 myotubes compared to appropriate controls. Hyperammonaemia in C2C12 myotubes resulted in impaired intact cell respiration, reduced complex I/NADH oxidase activity and electron leak occurring at complex III of the electron transport chain. Consistently, lower NAD+ /NADH ratio was observed during hyperammonaemia with reduced TCA cycle intermediates compared to controls. Generation of reactive oxygen species resulted in increased content of skeletal muscle carbonylated proteins and thiobarbituric acid reactive substances during hyperammonaemia. A cell-permeable ester of α-ketoglutarate reversed the low TCA cycle intermediates and ATP content in myotubes during hyperammonaemia. However, the mitochondrial antioxidant MitoTEMPO did not reverse the lower ATP content during hyperammonaemia. We provide for the first time evidence that skeletal muscle hyperammonaemia results in mitochondrial dysfunction and oxidative stress. Use of anaplerotic substrates to reverse ammonia-induced mitochondrial dysfunction is a novel therapeutic approach.


Assuntos
Hiperamonemia/metabolismo , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Estresse Oxidativo , Trifosfato de Adenosina/metabolismo , Idoso , Animais , Linhagem Celular , Respiração Celular , Creatina Quinase/metabolismo , Feminino , Humanos , Cirrose Hepática/metabolismo , Masculino , Pessoa de Meia-Idade , Cadeias Pesadas de Miosina/metabolismo , NAD/metabolismo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
4.
bioRxiv ; 2024 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-39463972

RESUMO

Cardiovascular disease and heart failure are a major health challenge, with sex differences in pathophysiology and treatment responses critically influencing patient outcomes. G protein-coupled receptor (GPCR) kinase 2 (GRK2) is a pivotal regulator of cellular signaling whose elevation is a hallmark of heart failure progression. Its complex network of protein interactions impact a wide range of physiological and pathophysiological processes including cardiac function. In this study, we examined the effects of cardiac-restricted expression of an amino-terminal peptide of GRK2 (ßARKnt) in female mice subjected to acute and chronic pressure overload. Our findings reveal that that ßARKnt affects hypertrophy development and cardiac function differently in female mice than in males, leading to a transition to heart failure not observed in control females or ßARKnt males. Notably, the ßARKnt female mice exhibited baseline hypertrophy with distinct left atrial morphology, increased fibrosis, and immune cell infiltration compared to the controls, which progressed under chronic stress, indicating adverse cardiac remodeling. Furthermore, ßARKnt female mice, unlike males, exhibit impaired tissue respiration following acute pressure overload and altered glucose sensitivity and insulin tolerance, highlighting significant remodeling of cardiac and systemic metabolism.

5.
Heart Rhythm ; 20(9): 1219-1226, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37329937

RESUMO

BACKGROUND: Genomewide association studies have associated >100 genetic loci with atrial fibrillation (AF), but establishing causal genes contributing to AF remains challenging. OBJECTIVE: The purpose of this study was to determine candidate novel causal genes and mechanistic pathways associated with AF risk loci by incorporating gene expression and coexpression analyses and to provide a resource for functional studies and targeting of AF-associated genes. METHODS: Cis-expression quantitative trait loci were identified for candidate genes near AF risk variants in human left atrial tissues. Coexpression partners were identified for each candidate gene. Weighted gene coexpression network analysis (WGCNA) identified modules and modules with overrepresentation of candidate AF genes. Ingenuity pathway analysis (IPA) was applied to the coexpression partners of each candidate gene. IPA and gene set over representation analysis were applied to each WGCNA module. RESULTS: One hundred sixty-six AF-risk single nucleotide polymorphisms were located in 135 loci. Eighty-one novel genes not previously annotated as putative AF risk genes were identified. IPA identified mitochondrial dysfunction, oxidative stress, epithelial adherens junction signaling, and sirtuin signaling as the most frequent significant pathways. WGCNA characterized 64 modules (candidate AF genes overrepresented in 8), represented by cell injury, death, stress, developmental, metabolic/mitochondrial, transcription/translation, and immune activation/inflammation regulatory pathways. CONCLUSION: Candidate gene coexpression analyses suggest significant roles for cellular stress and remodeling in AF, supporting a dual risk model for AF: Genetic susceptibility to AF may not manifest until later in life, when cellular stressors overwhelm adaptive responses. These analyses also provide a novel resource to guide functional studies on potential causal AF genes.


Assuntos
Apêndice Atrial , Fibrilação Atrial , Humanos , Átrios do Coração , Transcrição Gênica , Predisposição Genética para Doença
6.
Cell Rep Med ; 3(10): 100749, 2022 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-36223777

RESUMO

Effective drugs for atrial fibrillation (AF) are lacking, resulting in significant morbidity and mortality. This study demonstrates that network proximity analysis of differentially expressed genes from atrial tissue to drug targets can help prioritize repurposed drugs for AF. Using enrichment analysis of drug-gene signatures and functional testing in human inducible pluripotent stem cell (iPSC)-derived atrial-like cardiomyocytes, we identify metformin as a top repurposed drug candidate for AF. Using the active compactor, a new design analysis of large-scale longitudinal electronic health record (EHR) data, we determine that metformin use is significantly associated with a reduced risk of AF (odds ratio = 0.48, 95%, confidence interval [CI] 0.36-0.64, p < 0.001) compared with standard treatments for diabetes. This study utilizes network medicine methodologies to identify repurposed drugs for AF treatment and identifies metformin as a candidate drug.


Assuntos
Fibrilação Atrial , Metformina , Humanos , Fibrilação Atrial/tratamento farmacológico , Metformina/farmacologia , Transcriptoma , Átrios do Coração
7.
J Mol Cell Cardiol ; 46(6): 883-90, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19265702

RESUMO

Previous studies have reported that elevated myocardial lipids in a model of mild-to-moderate heart failure increased mitochondrial function, but did not alter left ventricular function. Whether more prolonged exposure to high dietary lipids would promote a lipotoxic phenotype in mitochondrial and myocardial contractile function has not been determined. We tested the hypothesis that prolonged exposure to high dietary lipids, following coronary artery ligation, would preserve myocardial and mitochondrial function in heart failure. Rats underwent ligation or sham surgery and were fed normal (10% kcal fat) (SHAM, HF) or high fat diet (60% kcal saturated fat) (SHAM+FAT, HF+FAT) for sixteen weeks. Although high dietary fat was accompanied by myocardial tissue triglyceride accumulation (SHAM 1.47+/-0.14; SHAM+FAT 2.32+/-0.14; HF 1.34+/-0.14; HF+FAT 2.21+/-0.20 micromol/gww), fractional shortening was increased 16% in SHAM+FAT and 28% in HF+FAT compared to SHAM and HF, respectively. Despite increased medium-chain acyl-CoA dehydrogenase (MCAD) activity in interfibrillar mitochondria (IFM) of both SHAM+FAT and HF+FAT, dietary lipids also were associated with decreased state 3 respiration using palmitoylcarnitine (SHAM 369+/-14; SHAM+FAT 307+/-23; HF 354+/-13; HF+FAT 366+/-18 nAO min(-1) mg(-1)) in SHAM+FAT compared to SHAM and HF+FAT. State 3 respiration in IFM also was decreased in SHAM+FAT relative to SHAM using succinate and DHQ. In conclusion, high dietary lipids promoted myocardial lipid accumulation, but were not accompanied by alterations in myocardial contractile function typically associated with lipotoxicity. In normal animals, high dietary fat decreased mitochondrial respiration, but also increased MCAD activity. These studies support the concept that high fat feeding can modify multiple cellular pathways that differentially affect mitochondrial function under normal and pathological conditions.


Assuntos
Gorduras na Dieta/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Acil-CoA Desidrogenase , Acil-CoA Desidrogenase de Cadeia Longa , Adiponectina/sangue , Animais , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Butiril-CoA Desidrogenase , Gorduras na Dieta/administração & dosagem , Ecocardiografia , Ensaio de Imunoadsorção Enzimática , Ácidos Graxos não Esterificados/sangue , Hemodinâmica/efeitos dos fármacos , Insulina/sangue , Leptina/sangue , Masculino , Proteínas Mitocondriais/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Wistar
8.
Cardiovasc Res ; 79(2): 331-40, 2008 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-18339649

RESUMO

AIMS: Heart failure is associated with decreased myocardial fatty acid oxidation capacity and has been likened to energy starvation. Increased fatty acid availability results in an induction of genes promoting fatty acid oxidation. The aim of the present study was to investigate possible mechanisms by which high fat feeding improved mitochondrial and contractile function in heart failure. METHODS AND RESULTS: Male Wistar rats underwent coronary artery ligation (HF) or sham surgery and were immediately fed either a normal (14% kcal fat) (SHAM, HF) or high-fat diet (60% kcal saturated fat) (SHAM+FAT, HF+FAT) for 8 weeks. Mitochondrial respiration and gene expression and enzyme activities of fatty acid-regulated mitochondrial genes and proteins were assessed. Subsarcolemmal (SSM) and interfibrillar mitochondria were isolated from the left ventricle. State 3 respiration using lipid substrates octanoylcarnitine and palmitoylcarnitine increased in the SSM of HF+FAT compared with SHAM+FAT and HF, respectively (242 +/- 21, 246 +/- 21 vs. 183 +/- 8, 181 +/- 6 and 193 +/- 17, 185 +/- 16 nAO min(-1) mg(-1)). Despite decreased medium-chain acyl-CoA dehydrogenase (MCAD) mRNA in HF and HF+FAT, MCAD protein was not altered, and MCAD activity increased in HF+FAT (HF, 65.1 +/- 2.7 vs. HF+FAT, 81.5 +/- 5.4 nmoles min(-1) mg(-1)). Activities of short- and long-chain acyl-CoA dehydrogenase also were elevated and correlated to increased state 3 respiration. This was associated with an improvement in myocardial contractility as assessed by left ventricular +dP/dt max. CONCLUSION: Administration of a high-fat diet increased state 3 respiration and acyl-CoA dehydrogenase activities, but did not normalize mRNA or protein levels of acyl-CoA dehydrogenases in coronary artery ligation-induced heart failure rats.


Assuntos
Acil-CoA Desidrogenase/metabolismo , Insuficiência Cardíaca/enzimologia , Insuficiência Cardíaca/fisiopatologia , Mitocôndrias Cardíacas/metabolismo , Contração Miocárdica/fisiologia , Adiponectina/metabolismo , Animais , Glicemia/metabolismo , Carnitina/análogos & derivados , Carnitina/metabolismo , Gorduras na Dieta/farmacologia , Modelos Animais de Doenças , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Insulina/metabolismo , Leptina/metabolismo , Masculino , Contração Miocárdica/efeitos dos fármacos , Ratos , Ratos Wistar , Triglicerídeos/metabolismo
9.
Eur J Heart Fail ; 8(7): 687-93, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16513421

RESUMO

Studies in advanced heart failure show down-regulation of fatty acid oxidation genes, possibly due to decreased expression of the nuclear transcription factors peroxisome proliferator activated receptor alpha (PPARalpha) and retinoid X receptor alpha (RXRalpha). We assessed mRNA and protein expression of PPARalpha and RXRalpha, and for several PPAR/RXR regulated metabolic proteins at 8 and 20 weeks following myocardial infarction induced by coronary artery ligation. Infarction resulted in heart failure, as indicated by reduced LV fractional shortening and increased end diastolic area compared to sham. There was a progressive increase in LV end systolic area, myocardial ceramide content and atrial natriuretic peptide mRNA, and a deterioration in LV fractional area of shortening from 8 to 20 weeks. Protein and mRNA expression of PPARalpha and RXRalpha were not different among groups. The mRNA for PPAR/RXR regulated genes (e.g. medium chain acyl-CoA dehydrogenase (MCAD)) was down-regulated at 8 and 20 weeks post-infarction; however, neither the protein expression nor activity of MCAD was reduced compared to sham. In conclusion, reduced mRNA expression of PPAR/RXR regulated genes is not dependent on reduced PPAR/RXR protein expression.


Assuntos
Insuficiência Cardíaca/metabolismo , PPAR alfa/metabolismo , Receptor X Retinoide alfa/metabolismo , Acil-CoA Desidrogenase/metabolismo , Animais , Modelos Animais de Doenças , Regulação para Baixo , Regulação da Expressão Gênica , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/enzimologia , Insuficiência Cardíaca/fisiopatologia , Masculino , PPAR alfa/genética , RNA Mensageiro/análise , Ratos , Ratos Wistar , Receptor X Retinoide alfa/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ultrassonografia
11.
Cardiovasc Res ; 89(4): 852-61, 2011 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-21123218

RESUMO

AIMS: Pre-treatment with dietary ω3 polyunsaturated fatty acids (ω3-PUFA) has been reported to reduce the incidence of new-onset atrial fibrillation (AF) following cardiac surgery. In a canine cardiac surgery model, we evaluated the impact of dietary ω3-PUFA on atrial electrophysiological properties, inflammatory markers, the atrial endothelin-1 (ET-1) system, and the expression and distribution of connexin 43. METHODS AND RESULTS: Adult mongrel dogs received either normal chow (NC, n = 11) or chow supplemented with fish oil (FO, 0.6 g ω3-PUFA/kg/day, n = 9) for 3 weeks before surgery. A left thoracotomy was performed, and the left atrial appendage (LAA) was excised. Atrial pacing/recording wires were placed, and the pericardium/chest was closed. The atrial ratio of ω6/ω3 lipids decreased from 15-20 in NC to 2-3 in FO. FO treatment lowered pre-surgical and stabilized post-surgical arachidonate levels. Peak neutrophil to lymphocyte ratio was lower and decayed faster in FO-treated animals. Extensive inflammatory cell infiltration was present in NC atria, but was reduced in FO-treated dogs. FO-treated animals had lower post-surgical atrial expression of inducible nitric oxide synthase (iNOS) and reduced plasma ET-1. Expression of ET-1 and inositol trisphosphate receptor type-2 proteins in the LAA was also reduced. FO treatment prolonged post-operative atrial effective refractory period, slowed heart rate, and enhanced heart rate variability. Importantly, AF (>30 s) was inducible in four of six NC dogs, but no FO dogs. CONCLUSION: Dietary FO attenuated AF inducibility following cardiac surgery by modulating autonomic tone and heart rate. FO also reduced atrial inflammation, iNOS, and ET-1 expression.


Assuntos
Fibrilação Atrial/prevenção & controle , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Ácidos Graxos Ômega-3/administração & dosagem , Complicações Pós-Operatórias/prevenção & controle , Animais , Proteína C-Reativa/análise , Conexina 43/análise , Conexina 43/metabolismo , Cães , Endotelina-1/análise , Feminino , Frequência Cardíaca , Receptores de Inositol 1,4,5-Trifosfato/análise , Lipídeos/sangue , Masculino , Óxido Nítrico Sintase Tipo II/análise , Peroxidase/análise , Fosforilação , Receptores de Endotelina/análise
12.
Am J Physiol Heart Circ Physiol ; 294(2): H1036-47, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18156197

RESUMO

Virtually every mammalian cell, including cardiomyocytes, possesses an intrinsic circadian clock. The role of this transcriptionally based molecular mechanism in cardiovascular biology is poorly understood. We hypothesized that the circadian clock within the cardiomyocyte influences diurnal variations in myocardial biology. We, therefore, generated a cardiomyocyte-specific circadian clock mutant (CCM) mouse to test this hypothesis. At 12 wk of age, CCM mice exhibit normal myocardial contractile function in vivo, as assessed by echocardiography. Radiotelemetry studies reveal attenuation of heart rate diurnal variations and bradycardia in CCM mice (in the absence of conduction system abnormalities). Reduced heart rate persisted in CCM hearts perfused ex vivo in the working mode, highlighting the intrinsic nature of this phenotype. Wild-type, but not CCM, hearts exhibited a marked diurnal variation in responsiveness to an elevation in workload (80 mmHg plus 1 microM epinephrine) ex vivo, with a greater increase in cardiac power and efficiency during the dark (active) phase vs. the light (inactive) phase. Moreover, myocardial oxygen consumption and fatty acid oxidation rates were increased, whereas cardiac efficiency was decreased, in CCM hearts. These observations were associated with no alterations in mitochondrial content or structure and modest mitochondrial dysfunction in CCM hearts. Gene expression microarray analysis identified 548 and 176 genes in atria and ventricles, respectively, whose normal diurnal expression patterns were altered in CCM mice. These studies suggest that the cardiomyocyte circadian clock influences myocardial contractile function, metabolism, and gene expression.


Assuntos
Ritmo Circadiano/genética , Ritmo Circadiano/fisiologia , Expressão Gênica/fisiologia , Contração Miocárdica/fisiologia , Miocárdio/metabolismo , Miócitos Cardíacos/fisiologia , Animais , DNA/biossíntese , DNA/genética , Ecocardiografia , Eletrocardiografia , Frequência Cardíaca/fisiologia , Técnicas In Vitro , Camundongos , Mitocôndrias Cardíacas/fisiologia , Proteínas Musculares/metabolismo , Contração Miocárdica/genética , Análise de Sequência com Séries de Oligonucleotídeos , Perfusão , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/fisiologia , Telemetria
13.
Am J Physiol Heart Circ Physiol ; 293(3): H1609-16, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17545473

RESUMO

Clinical studies have shown a greater incidence of myocardial infarction in diabetic patients, and following an infarction, diabetes is associated with an increased risk for the development of left ventricular (LV) dysfunction and heart failure. The goal of this study was to determine if the progression of heart failure following myocardial infarction in type 2 diabetic (T2D) rats is accelerated compared with nondiabetic rats. Male nondiabetic Wistar-Kyoto (WKY) and T2D Goto-Kakizaki (GK) rats underwent coronary artery ligation or sham surgery to induce heart failure. Postligation (8 and 20 wk), two-dimensional echocardiography and LV pressure measurements were made. Heart failure progression, as assessed by enhanced LV remodeling and contractile dysfunction, was accelerated 8 wk postligation in the T2D animals. LV remodeling was evident from increased end-diastolic and end-systolic diameters and areas in the GK compared with the WKY infarcted group. Furthermore, enhanced LV contractile dysfunction was evident from a greater deterioration in fractional shortening and enhanced myocardial performance index (an index of global LV dysfunction) in the GK infarcted group. This accelerated progression was accompanied by greater increases in atrial natriuretic factor and skeletal alpha-actin (gene markers of heart failure and hypertrophy) mRNA levels in GK infarcted hearts. Despite similar decreases in metabolic gene expression (i.e., peroxisome proliferator-activated receptor-alpha-regulated genes associated with fatty acid oxidation) between infarcted WKY and GK rat hearts, myocardial triglyceride levels were elevated in the GK hearts only. These results, demonstrating enhanced remodeling and LV dysfunction 8 wk postligation provide evidence of an accelerated progression of heart failure in T2D rats.


Assuntos
Baixo Débito Cardíaco/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Infarto do Miocárdio/fisiopatologia , Actinas/genética , Actinas/metabolismo , Animais , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Glicemia/metabolismo , Baixo Débito Cardíaco/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Ácidos Graxos não Esterificados/sangue , Frequência Cardíaca/fisiologia , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos , Ratos Endogâmicos WKY , Disfunção Ventricular Esquerda , Remodelação Ventricular
14.
Clin Exp Pharmacol Physiol ; 34(1-2): 113-9, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17201745

RESUMO

1. Cardiac lipotoxicity is characterized by hypertrophy and contractile dysfunction and can be triggered by impaired mitochondrial fatty acid oxidation and lipid accumulation. The present study investigated the effect of dietary fatty acid intake alone and in combination with inhibition of mitochondrial fatty acid uptake with the carnitine palmitoyl transferase (CPT)-I inhibitor oxfenicine. Long-chain fatty acids activate peroxisome proliferator-activated receptors (PPAR), thus mRNA levels of PPAR target genes were measured. 2. Rats were untreated or given the CPT-I inhibitor oxfenicine (150 mg/kg per day) and were fed for 8 weeks with either: (i) standard low-fat chow (10% of energy from fat); (ii) a long-chain saturated fatty acid diet; (iii) a long-chain unsaturated fatty acid diet; or (iv) a medium-chain fatty acid diet (which bypasses CPT-I). High-fat diets contained 60% of energy from fat. 3. Cardiac triglyceride content was increased in the absence of oxfenicine in the saturated fat group compared with other diets. Oxfenicine treatment further increased cardiac triglyceride stores in the saturated fat group and caused a significant increase in the unsaturated fat group. Despite elevations in triglyceride stores, left ventricular mass, end diastolic volume and systolic function were unaffected. 4. The mRNA levels of PPAR-regulated genes were increased by the high saturated and unsaturated fat diets compared with standard chow or the medium chain fatty acid chow. Oxfenicine did not further upregulate PPARalpha target genes within each dietary treatment group. 5. Taken together, the data suggest that consuming a high-fat diet or inhibiting CPT-I do not result in cardiac hypertrophy or cardiac dysfunction in normal rats.


Assuntos
Carnitina O-Palmitoiltransferase/antagonistas & inibidores , Gorduras na Dieta/farmacologia , Inibidores Enzimáticos/farmacologia , Glicina/análogos & derivados , Acil-CoA Desidrogenase/genética , Acil-CoA Desidrogenase/metabolismo , Animais , Cardiomegalia/etiologia , Citrato (si)-Sintase/metabolismo , Ácidos Graxos não Esterificados/sangue , Glicina/farmacologia , Insulina/sangue , Canais Iônicos/genética , Leptina/sangue , Masculino , Proteínas Mitocondriais/genética , Miocárdio/metabolismo , PPAR alfa/metabolismo , Proteínas Quinases/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Triglicerídeos/sangue , Proteína Desacopladora 3
15.
Am J Physiol Heart Circ Physiol ; 292(3): H1498-506, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17114240

RESUMO

Lipid accumulation in nonadipose tissue due to enhanced circulating fatty acids may play a role in the pathophysiology of heart failure, obesity, and diabetes. Accumulation of myocardial lipids and related intermediates, e.g., ceramide, is associated with decreased contractile function, mitochondrial oxidative phosphorylation, and electron transport chain (ETC) complex activities. We tested the hypothesis that the progression of heart failure would be exacerbated by elevated myocardial lipids and an associated ceramide-induced inhibition of mitochondrial oxidative phosphorylation and ETC complex activities. Heart failure (HF) was induced by coronary artery ligation. Rats were then randomly assigned to either a normal (10% kcal from fat; HF, n = 8) or high saturated fat diet (60% kcal from saturated fat; HF + Sat, n = 7). Sham-operated animals (sham; n = 8) were fed a normal diet. Eight weeks postligation, left ventricular (LV) function was assessed by echocardiography and catheterization. Subsarcolemmal and interfibrillar mitochondria were isolated from the LV. Heart failure resulted in impaired LV contractile function [decreased percent fractional shortening and peak rate of LV pressure rise and fall (+/-dP/dt)] and remodeling (increased end-diastolic and end-systolic dimensions) in HF compared with sham. No further progression of LV dysfunction was evident in HF + Sat. Mitochondrial state 3 respiration was increased in HF + Sat compared with HF despite elevated myocardial ceramide. Activities of ETC complexes II and IV were elevated in HF + Sat compared with HF and sham. High saturated fat feeding following coronary artery ligation was associated with increased oxidative phosphorylation and ETC complex activities and did not adversely affect LV contractile function or remodeling, despite elevations in myocardial ceramide.


Assuntos
Gorduras na Dieta , Mitocôndrias Cardíacas/metabolismo , Infarto do Miocárdio/fisiopatologia , Função Ventricular Esquerda/fisiologia , Animais , Vasos Coronários/fisiopatologia , Modelos Animais de Doenças , Ecocardiografia , Transporte de Elétrons , Mitocôndrias Cardíacas/efeitos dos fármacos , Fosforilação Oxidativa , Ratos , Disfunção Ventricular Esquerda/fisiopatologia
16.
Am J Physiol Heart Circ Physiol ; 290(5): H1899-904, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16339830

RESUMO

Intracardiac accumulation of lipid and related intermediates (e.g., ceramide) is associated with cardiac dysfunction and may contribute to the progression of heart failure (HF). Overexpression of nuclear receptor peroxisome proliferator-activated receptor-alpha (PPARalpha) increases intramyocellular ceramide and left ventricular (LV) dysfunction. We tested the hypothesis that activation of fatty acid metabolism with fat feeding or a PPARalpha agonist increases myocardial triglyceride and/or ceramide and exacerbates LV dysfunction in HF. Rats with infarct-induced HF (n = 38) or sham-operated rats (n = 10) were either untreated (INF, n = 10), fed a high-fat diet (45% kcal fat, INF + Fat, n = 15), or fed the PPARalpha agonist fenofibrate (150 mg.kg(-1).day(-1), INF + Feno, n = 13) for 12 wk. LV ejection fraction was significantly reduced with HF (49 +/- 6%) compared with sham operated (86 +/- 2%) with no significant differences in ejection fraction (or other functional or hemodynamic measures) among the three infarcted groups. Treatment with the PPARalpha agonist resulted in LV hypertrophy (24% increase in LV/body mass ratio) and induced mRNAs encoding for PPARalpha-regulated genes, as well as protein expression and activity of medium chain acyl-CoA dehydrogenase (compared with INF and INF + Fat groups). Myocardial ceramide content was elevated in the INF group compared with sham-operated rats, with no further change in the INF + Fat or INF + Feno groups. Myocardial triglyceride was unaffected by infarction but increased in the INF + Fat group. In conclusion, LV dysfunction and dilation are not worsened despite upregulation of the fatty acid metabolic pathway and LV hypertrophy or accumulation of myocardial triglyceride in the rat infarct model of HF.


Assuntos
Gorduras na Dieta/metabolismo , Insuficiência Cardíaca/fisiopatologia , Infarto do Miocárdio/fisiopatologia , PPAR alfa/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia , Animais , Ceramidas/metabolismo , Modelos Animais de Doenças , Comportamento Alimentar/fisiologia , Fenofibrato/administração & dosagem , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Hipolipemiantes/administração & dosagem , Masculino , Infarto do Miocárdio/complicações , Infarto do Miocárdio/tratamento farmacológico , PPAR alfa/agonistas , Ratos , Ratos Wistar , Fatores de Tempo , Resultado do Tratamento , Regulação para Cima , Disfunção Ventricular Esquerda/complicações , Disfunção Ventricular Esquerda/tratamento farmacológico
17.
Am J Physiol Heart Circ Physiol ; 291(1): H38-44, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16443671

RESUMO

Fatty acids are the primary fuel for the heart and are ligands for peroxisome proliferator-activated receptors (PPARs), which regulate the expression of genes encoding proteins involved in fatty acid metabolism. Saturated fatty acids, particularly palmitate, can be converted to the proapoptotic lipid intermediate ceramide. This study assessed cardiac function, expression of PPAR-regulated genes, and cardiomyocyte apoptosis in rats after 8 wk on either a low-fat diet [normal chow control (NC); 10% fat calories] or high-fat diets composed mainly of either saturated (Sat) or unsaturated fatty acids (Unsat) (60% fat calories) (n = 10/group). The Sat group had lower plasma insulin and leptin concentrations compared with the NC or Unsat groups. Cardiac function and mass and body mass were not different. Cardiac triglyceride content was increased in the Sat and Unsat groups compared with NC (P < 0.05); however, ceramide content was higher in the Sat group compared with the Unsat group (2.9 +/- 0.2 vs. 1.4 +/- 0.2 nmol/g; P < 0.05), whereas the NC group was intermediate (2.3 +/- 0.3 nmol/g). The number of apoptotic myocytes, assessed by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling staining, was higher in the Sat group compared with the Unsat group (0.28 +/- 0.05 vs. 0.17 +/- 0.04 apoptotic cells/1,000 nuclei; P < 0.04) and was positively correlated to ceramide content (P < 0.02). Both high-fat diets increased the myocardial mRNA expression of the PPAR-regulated genes encoding uncoupling protein-3 and pyruvate dehydrogenase kinase-4, but only the Sat diet upregulated medium-chain acyl-CoA dehydrogenase. In conclusion, dietary fatty acid composition affects cardiac ceramide accumulation, cardiomyocyte apoptosis, and expression of PPAR-regulated genes independent of cardiac mass or function.


Assuntos
Tecido Adiposo/fisiologia , Constituição Corporal/fisiologia , Gorduras na Dieta/farmacologia , Leptina/sangue , Miócitos Cardíacos/fisiologia , Tecido Adiposo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Constituição Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Células Cultivadas , Gorduras Insaturadas na Dieta/farmacologia , Ácidos Graxos/farmacologia , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Ratos , Ratos Wistar
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