RESUMO
Perturbed vitamin-A metabolism is associated with type 2 diabetes and mitochondrial dysfunction that are pathophysiologically linked to the development of diabetic cardiomyopathy (DCM). However, the mechanism, by which vitamin A might regulate mitochondrial energetics in DCM has previously not been explored. To test the hypothesis that vitamin-A deficiency accelerates the onset of cardiomyopathy in diet-induced obesity (DIO), we subjected mice with lecithin retinol acyltransferase (Lrat) germline deletion, which exhibit impaired vitamin-A stores, to vitamin A-deficient high-fat diet (HFD) feeding. Wild-type mice fed with a vitamin A-sufficient HFD served as controls. Cardiac structure, contractile function, and mitochondrial respiratory capacity were preserved despite vitamin-A deficiency following 20 wk of HFD feeding. Gene profiling by RNA sequencing revealed that vitamin A is required for the expression of genes involved in cardiac fatty acid oxidation, glycolysis, tricarboxylic acid cycle, and mitochondrial oxidative phosphorylation in DIO as expression of these genes was relatively preserved under vitamin A-sufficient HFD conditions. Together, these data identify a transcriptional program, by which vitamin A preserves cardiac energetic gene expression in DIO that might attenuate subsequent onset of mitochondrial and contractile dysfunction.NEW & NOTEWORTHY The relationship between vitamin-A status and the pathogenesis of diabetic cardiomyopathy has not been studied in detail. We assessed cardiac mitochondrial respiratory capacity, contractile function, and gene expression by RNA sequencing in a murine model of combined vitamin-A deficiency and diet-induced obesity. Our study identifies a role for vitamin A in preserving cardiac energetic gene expression that might attenuate subsequent development of mitochondrial and contractile dysfunction in diet-induced obesity.
Assuntos
Diabetes Mellitus Tipo 2 , Cardiomiopatias Diabéticas , Camundongos , Animais , Vitamina A , Modelos Animais de Doenças , Dieta , Obesidade/genética , Expressão Gênica , VitaminasRESUMO
BACKGROUND: There is scarce evidence for mechanical circulatory support (MCS) in patients with influenza-related myocarditis complicated by refractory cardiogenic shock (rCS). We sought to investigate the impact of MCS using combined veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and micro-axial flow pumps (the ECMELLA concept) in influenza-related myocarditis complicated by rCS. METHODS: This is a prospective, observational analysis from the single centre HAnnover Cardiac Unloading REgistry (HACURE) from two recent epidemic influenza seasons. We analysed patients with verified influenza-associated myocarditis complicated by rCS who were admitted to our intensive care unit (ICU) on MCS. Subsequently, we performed a propensity score (PS) matched analysis to patients with acute myocardial infarction (AMI) complicated by rCS and non-ischaemic cardiomyopathy (DCM) related rCS. RESULTS: We describe a series of seven patients with rCS-complicated influenza-related myocarditis (mean age 56±10â years, 58% male, influenza A (n=2)/influenza B (n=5)). No patient had been vaccinated prior to the influenza season. MCS was provided using combined VA-ECMO and Impella micro-axial flow pump. In two patients with out-of-hospital cardiac arrest, VA-ECMO had been implanted for extracorporeal cardiopulmonary resuscitation. All patients died within 18â days of hospital admission. By PS-based comparison to patients with AMI- or DCM-related rCS and combined MCS, 30-day mortality was significantly higher in influenza-related rCS. CONCLUSION: Despite initial stabilisation with combined MCS in patients with rCS-complicated influenza-related myocarditis, the detrimental course of shock could not be stopped and all patients died. Influenza virus infection potentially critically affects other organs besides the heart, leading to irreversible end-organ damage that MCS cannot compensate for and, therefore, results in a devastating outcome.
Assuntos
Miocardite , Orthomyxoviridae , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miocardite/complicações , Miocardite/terapia , Estudos Prospectivos , Choque Cardiogênico/etiologia , Choque Cardiogênico/terapia , Resultado do TratamentoRESUMO
BACKGROUND: Late Fontan survivors are at high risk to experience heart failure and death. Therefore, the current study sought to investigate the role of non-invasive diagnostics as prognostic markers for failure of the systemic ventricle following Fontan procedure. METHODS: This monocentric, longitudinal observational study included 60 patients with a median age of 24.5 (19-29) years, who were subjected to cardiac magnetic resonance imaging, echocardiography, cardiopulmonary exercise testing, and blood analysis. The primary endpoint of this study was decompensated heart failure with symptoms at rest, peripheral and/or pulmonary edema, and/or death. RESULTS: During a follow-up of 24 months, 5 patients died and 5 patients suffered from decompensated heart failure. Clinical (NYHA class, initial surgery), functional (VO2 peak, ejection fraction, cardiac index), circulating biomarkers (N-terminal pro brain natriuretic peptide), and imaging parameters (end diastolic volume index, end systolic volume index, mass-index, contractility, afterload) were significantly related to the primary endpoint. Multi-variate regression analysis identified afterload as assessed by cardiac magnetic resonance imaging as an independent predictor of the primary endpoint (hazard ratio 1.98, 95% confidence interval 1.19-3.29, p = 0.009). CONCLUSION: We identified distinct parameters of cardiopulmonary exercise testing, cardiac magnetic resonance imaging, and blood testing as markers for future decompensated heart failure and death in patients with Fontan circulation. Importantly, our data also identify increased afterload as an independent predictor for increased morbidity and mortality. This parameter is easy to assess by non-invasive cardiac magnetic resonance imaging. Its modulation may represent a potential therapeutic approach target in these high-risk patients.
Assuntos
Técnica de Fontan , Cardiopatias Congênitas/cirurgia , Insuficiência Cardíaca/mortalidade , Adulto , Biomarcadores/sangue , Teste de Esforço , Feminino , Alemanha , Cardiopatias Congênitas/fisiopatologia , Insuficiência Cardíaca/diagnóstico por imagem , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Análise Multivariada , Prognóstico , Análise de Regressão , Volume Sistólico , Adulto JovemRESUMO
Diabetes mellitus increases the risk of heart failure independent of co-existing hypertension and coronary artery disease. Although several molecular mechanisms for the development of diabetic cardiomyopathy have been identified, they are incompletely understood. The pathomechanisms are multifactorial and as a consequence, no causative treatment exists at this time to modulate or reverse the molecular changes contributing to accelerated cardiac dysfunction in diabetic patients. Numerous animal models have been generated, which serve as powerful tools to study the impact of type 1 and type 2 diabetes on the heart. Despite specific limitations of the models generated, they mimic various perturbations observed in the diabetic myocardium and continue to provide important mechanistic insight into the pathogenesis underlying diabetic cardiomyopathy. This article reviews recent studies in both diabetic patients and in these animal models, and discusses novel hypotheses to delineate the increased incidence of heart failure in diabetic patients.
Assuntos
Diabetes Mellitus Experimental , Cardiomiopatias Diabéticas , Animais , Humanos , CamundongosRESUMO
Heart failure is associated with generalized insulin resistance. Moreover, insulin-resistant states such as type 2 diabetes mellitus and obesity increases the risk of heart failure even after adjusting for traditional risk factors. Insulin resistance or type 2 diabetes mellitus alters the systemic and neurohumoral milieu, leading to changes in metabolism and signaling pathways in the heart that may contribute to myocardial dysfunction. In addition, changes in insulin signaling within cardiomyocytes develop in the failing heart. The changes range from activation of proximal insulin signaling pathways that may contribute to adverse left ventricular remodeling and mitochondrial dysfunction to repression of distal elements of insulin signaling pathways such as forkhead box O transcriptional signaling or glucose transport, which may also impair cardiac metabolism, structure, and function. This article will review the complexities of insulin signaling within the myocardium and ways in which these pathways are altered in heart failure or in conditions associated with generalized insulin resistance. The implications of these changes for therapeutic approaches to treating or preventing heart failure will be discussed.
Assuntos
Insuficiência Cardíaca/fisiopatologia , Insulina/fisiologia , Animais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Gorduras na Dieta/toxicidade , Modelos Animais de Doenças , Progressão da Doença , Células Endoteliais/metabolismo , Ácidos Graxos/metabolismo , Previsões , Glucose/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/prevenção & controle , Insuficiência Cardíaca/terapia , Humanos , Hiperinsulinismo/fisiopatologia , Resistência à Insulina/fisiologia , Mitocôndrias Cardíacas/fisiologia , Isquemia Miocárdica/complicações , Isquemia Miocárdica/fisiopatologia , Miócitos Cardíacos/metabolismo , Miócitos de Músculo Liso/metabolismo , Obesidade/complicações , Obesidade/fisiopatologia , Transporte Proteico , Receptor de Insulina/fisiologia , Fatores de Risco , Transdução de Sinais/fisiologia , Remodelação Ventricular/fisiologiaRESUMO
BACKGROUND: Wolff-Parkinson-White (WPW) syndrome and idiopathic left ventricular tachycardia (ILVT) are rare and up to now the coexistence of both entities has rarely been reported. In patients with ventricular preexcitation the underlying mechanism of paroxysmal tachycardia most likely is atrioventricular reentrant tachycardia (AVRT). However, without ECG documentation of the tachycardia diagnosis of the underlying mechanism cannot be made due to similar clinical presentation of AVRT and ILVT. CASE PRESENTATION: We report a case of a two-staged occurrence of two rare arrhythmias in a young adult, who was admitted to our hospital twice within 6 months because of paroxysmal tachycardia. WPW syndrome and ILVT as underlying arrhythmias have been diagnosed and were ablated successfully. CONCLUSIONS: This case highlights the diagnostic defiance of rare tachycardia entities and the paramount importance of ECG documentation and analysis of all available tachycardia ECGs.
Assuntos
Ablação por Cateter/métodos , Eletrocardiografia , Taquicardia por Reentrada no Nó Atrioventricular/diagnóstico , Taquicardia Paroxística/diagnóstico , Taquicardia Ventricular/diagnóstico , Adulto , Diagnóstico Diferencial , Sistema de Condução Cardíaco/fisiopatologia , Sistema de Condução Cardíaco/cirurgia , Humanos , Masculino , Taquicardia por Reentrada no Nó Atrioventricular/complicações , Taquicardia por Reentrada no Nó Atrioventricular/cirurgia , Taquicardia Paroxística/complicações , Taquicardia Paroxística/cirurgia , Taquicardia Ventricular/complicações , Taquicardia Ventricular/cirurgia , Síndrome de Wolff-Parkinson-White/diagnósticoRESUMO
Exercise training is recognized to improve cardiac and skeletal muscle mitochondrial respiratory capacity; however, the impact of chronic exercise on vascular mitochondrial respiratory function is unknown. We hypothesized that exercise training concomitantly increases both vascular mitochondrial respiratory capacity and vascular function. Arteries from both sedentary (SED) and swim-trained (EX, 5 wk) mice were compared in terms of mitochondrial respiratory function, mitochondrial content, markers of mitochondrial biogenesis, redox balance, nitric oxide (NO) signaling, and vessel function. Mitochondrial complex I and complex I + II state 3 respiration and the respiratory control ratio (complex I + II state 3 respiration/complex I state 2 respiration) were greater in vessels from EX relative to SED mice, despite similar levels of arterial citrate synthase activity and mitochondrial DNA content. Furthermore, compared with the SED mice, arteries from EX mice displayed elevated transcript levels of peroxisome proliferative activated receptor-γ coactivator-1α and the downstream targets cytochrome c oxidase subunit IV isoform 1,isocitrate dehydrogenase(Idh)2, and Idh3a, increased manganese superoxide dismutase protein expression, increased endothelial NO synthase phosphorylation (Ser(1177)), and suppressed reactive oxygen species generation (all P< 0.05). Although there were no differences in EX and SED mice concerning endothelium-dependent and endothelium-independent vasorelaxation, phenylephrine-induced vasocontraction was blunted in vessels from EX compared with SED mice, and this effect was normalized by NOS inhibition. These training-induced increases in vascular mitochondrial respiratory capacity and evidence of improved redox balance, which may, at least in part, be attributable to elevated NO bioavailability, have the potential to protect against age- and disease-related challenges to arterial function.
Assuntos
Mitocôndrias Musculares/metabolismo , Músculo Liso Vascular/metabolismo , Condicionamento Físico Animal , Animais , Aorta/metabolismo , Aorta/fisiologia , Respiração Celular , Complexo IV da Cadeia de Transporte de Elétrons/genética , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/fisiologia , Óxido Nítrico Sintase Tipo III/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Vasoconstrição , VasodilataçãoRESUMO
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
Autophagy is a catabolic process involved in maintaining energy and organelle homeostasis. The relationship between obesity and the regulation of autophagy is cell type specific. Despite adverse consequences of obesity on cardiac structure and function, the contribution of altered cardiac autophagy in response to fatty acid overload is incompletely understood. Here, we report the suppression of autophagosome clearance and the activation of NADPH oxidase (Nox)2 in both high fat-fed murine hearts and palmitate-treated H9C2 cardiomyocytes (CMs). Defective autophagosome clearance is secondary to superoxide-dependent impairment of lysosomal acidification and enzyme activity in palmitate-treated CMs. Inhibition of Nox2 prevented superoxide overproduction, restored lysosome acidification and enzyme activity, and reduced autophagosome accumulation in palmitate-treated CMs. Palmitate-induced Nox2 activation was dependent on the activation of classical protein kinase Cs (PKCs), specifically PKCßII. These findings reveal a novel mechanism linking lipotoxicity with a PKCß-Nox2-mediated impairment in pH-dependent lysosomal enzyme activity that diminishes autophagic turnover in CMs.
Assuntos
Autofagia/efeitos dos fármacos , Gorduras na Dieta/farmacologia , Lisossomos/metabolismo , Glicoproteínas de Membrana/metabolismo , Miócitos Cardíacos/enzimologia , NADPH Oxidases/metabolismo , Ácido Palmítico/farmacologia , Animais , Autofagia/genética , Linhagem Celular , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/genética , Lisossomos/genética , Glicoproteínas de Membrana/genética , Camundongos , Miócitos Cardíacos/citologia , NADPH Oxidase 2 , NADPH Oxidases/genética , Proteína Quinase C beta/genética , Proteína Quinase C beta/metabolismo , Ratos , Superóxidos/metabolismoRESUMO
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
Autophagy is a conserved cellular process that plays an important role in cardiovascular homeostasis. Basal levels of autophagy are required for the maintenance of organellar quality control. Autophagy is dynamically regulated in the heart in the fasting to re-feeding transition. Insulin signaling plays an important role in the regulation of myocardial fuel metabolism, mitochondrial function and cellular growth. Recent studies have suggested an important role for insulin signaling in the regulation of myocardial autophagy. This dynamic regulation of autophagy induction during fasting may contribute to organellar homeostasis and if perturbed under conditions of hyperinsulinemia could contribute to accelerated cardiac aging.
Assuntos
Autofagia , Metabolismo Energético , Insulina/metabolismo , Mitocôndrias Cardíacas/metabolismo , Miocárdio/metabolismo , Transdução de Sinais , Animais , Humanos , Hiperinsulinismo/metabolismo , Hiperinsulinismo/patologia , Mitocôndrias Cardíacas/patologia , Miocárdio/patologiaRESUMO
BACKGROUND: Cardiogenic shock (CS) is the leading cause of death in patients with myocardial infarction with a mortality rate greater than 50%. Recently, the CS 4 Proteins (CS4P) and CLIP scores have been developed to predict survival in CS patients. However, their impact in acute CS and additional short-term left ventricular (LV) circulatory support as prognostic markers is currently not known. METHODS AND RESULTS: CS was induced in a porcine model by injecting microsphere particles into the left main coronary artery. Mechanical circulatory support was performed by additional percutaneous LV unloading using an Impella microaxial flow-pump for 30 minutes. Serum samples were collected at baseline, following the onset of CS, and additional LV unloading. Serum levels of biomarkers of the CS4P (beta-2-microglobulin, ALDOB, L-FABP, SerpinG1) and the CLIP scores (Cystatin C, Lactate, Interleukin-6, NT-proBNP) were neither different at any time point investigated nor did they correlate with cardiac output. CONCLUSION: The CS4P and CLIP scores do not reflect immediate whole-body dysregulation in acute CS and have not been able to predict the potential reversal following additional short-term mechanical support by LV unloading in our experimental model. The impact of both scores as prognostic markers after the immediate onset of CS and following additional short-term LV unloading to identify patients at greatest risk remains to be determined.
Assuntos
Coração Auxiliar , Infarto do Miocárdio , Humanos , Animais , Suínos , Choque Cardiogênico/diagnóstico , Choque Cardiogênico/terapia , Choque Cardiogênico/etiologia , Débito Cardíaco , Biomarcadores , Coração Auxiliar/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: Alveolar hypoxia is protective in the context of cardiovascular and ischemic heart disease; however, the underlying mechanisms are incompletely understood. The present study sought to test the hypothesis that hypoxia is cardioprotective in left ventricular pressure overload (LVPO)-induced heart failure. We furthermore aimed to test that overlapping mechanisms promote cardiac recovery in heart failure patients following left ventricular assist device-mediated mechanical unloading and circulatory support. METHODS AND RESULTS: We established a novel murine model of combined chronic alveolar hypoxia and LVPO following transverse aortic constriction (HxTAC). The HxTAC model is resistant to cardiac hypertrophy and the development of heart failure. The cardioprotective mechanisms identified in our HxTAC model include increased activation of HIF (hypoxia-inducible factor)-1α-mediated angiogenesis, attenuated induction of genes associated with pathological remodeling, and preserved metabolic gene expression as identified by RNA sequencing. Furthermore, LVPO decreased Tbx5 and increased Hsd11b1 mRNA expression under normoxic conditions, which was attenuated under hypoxic conditions and may induce additional hypoxia-mediated cardioprotective effects. Analysis of samples from patients with advanced heart failure that demonstrated left ventricular assist device-mediated myocardial recovery revealed a similar expression pattern for TBX5 and HSD11B1 as observed in HxTAC hearts. CONCLUSIONS: Hypoxia attenuates LVPO-induced heart failure. Cardioprotective pathways identified in the HxTAC model might also contribute to cardiac recovery following left ventricular assist device support. These data highlight the potential of our novel HxTAC model to identify hypoxia-mediated cardioprotective mechanisms and therapeutic targets that attenuate LVPO-induced heart failure and mediate cardiac recovery following mechanical circulatory support.
Assuntos
Estenose da Valva Aórtica , Insuficiência Cardíaca , Humanos , Camundongos , Animais , Insuficiência Cardíaca/etiologia , Cardiomegalia/metabolismo , Miocárdio/metabolismo , Hipóxia/complicações , Remodelação Ventricular , Modelos Animais de DoençasRESUMO
Mechanistic target of rapamycin (mTOR) is essential for cardiac development, growth, and function, but the role of mTOR in the regulation of cardiac metabolism and mitochondrial respiration is not well established. This study sought to determine cardiac metabolism and mitochondrial bioenergetics in mice with inducible deletion of mTOR in the adult heart. Doxycycline-inducible and cardiac-specific mTOR-deficient mice were generated by crossing cardiac-specific doxycycline-inducible tetO-Cre mice with mice harboring mTOR floxed alleles. Deletion of mTOR reduced mTORC1 and mTORC2 signaling after in vivo insulin stimulation. Maximum and minimum dP/dt measured by cardiac catheterization in vivo under anesthesia and cardiac output, cardiac power, and aortic pressure in ex vivo working hearts were unchanged, suggesting preserved cardiac function 4 wk after doxycycline treatment. However, myocardial palmitate oxidation was impaired, whereas glucose oxidation was increased. Consistent with reduced palmitate oxidation, expression of fatty acid metabolism genes fatty acid-binding protein 3, medium-chain acyl-CoA dehydrogenase, and hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein)-α and -ß was reduced, and carnitine palmitoyl transferase-1 and -2 enzymatic activity was decreased. Mitochondrial palmitoyl carnitine respiration was diminished. However, mRNA for peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α and -1ß, protein levels of PGC-1α, and electron transport chain subunits, mitochondrial DNA, and morphology were unchanged. Also, pyruvate-supported and FCCP-stimulated respirations were unchanged, suggesting that mTOR deletion induces a specific defect in fatty acid utilization. In conclusion, mTOR regulates mitochondrial fatty acid utilization but not glucose utilization in the heart via mechanisms that are independent of changes in PGC expression.
Assuntos
Ácidos Graxos/metabolismo , Mitocôndrias Cardíacas/metabolismo , Miocárdio/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Transativadores/metabolismo , Animais , Pressão Sanguínea , Débito Cardíaco , DNA Mitocondrial/metabolismo , Ácidos Graxos/genética , Coração/fisiologia , Metaboloma , Camundongos , Oxirredução , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Serina-Treonina Quinases TOR/genética , Transativadores/genética , Fatores de Transcrição , Transcrição GênicaRESUMO
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
Background: Perturbed mitochondrial energetics and vitamin A (VitA) metabolism are associated with the pathogenesis of diet-induced obesity (DIO) and type 2 diabetes (T2D). Methods: To test the hypothesis that VitA regulates tissue-specific mitochondrial energetics and adverse organ remodeling in DIO, we utilized a murine model of impaired VitA availability and high fat diet (HFD) feeding. Mitochondrial respiratory capacity and organ remodeling were assessed in liver, skeletal muscle, and kidney tissue, which are organs affected by T2D-associated complications and are critical for the pathogenesis of T2D. Results: In liver, VitA had no impact on maximal ADP-stimulated mitochondrial respiratory capacity (VADP) following HFD feeding with palmitoyl-carnitine and pyruvate each combined with malate as substrates. Interestingly, histopathological and gene expression analyses revealed that VitA mediates steatosis and adverse remodeling in DIO. In skeletal muscle, VitA did not affect VADP following HFD feeding. No morphological differences were detected between groups. In kidney, VADP was not different between groups with both combinations of substrates and VitA transduced the pro-fibrotic transcriptional response following HFD feeding. Conclusion: The present study identifies an unexpected and tissue-specific role for VitA in DIO that regulates the pro-fibrotic transcriptional response and that results in organ damage independent of changes in mitochondrial energetics.
Assuntos
Diabetes Mellitus Tipo 2 , Vitamina A , Camundongos , Animais , Vitamina A/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Mitocôndrias Musculares/metabolismo , Mitocôndrias/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Dieta Hiperlipídica/efeitos adversosRESUMO
AIMS: To determine the contribution of insulin signaling versus systemic metabolism to metabolic and mitochondrial alterations in type 1 diabetic hearts and test the hypothesis that antecedent mitochondrial dysfunction contributes to impaired cardiac efficiency (CE) in diabetes. METHODS AND RESULTS: Control mice (WT) and mice with cardiomyocyte-restricted deletion of insulin receptors (CIRKO) were rendered diabetic with streptozotocin (WT-STZ and CIRKO-STZ, respectively), non-diabetic controls received vehicle (citrate buffer). Cardiac function was determined by echocardiography; myocardial metabolism, oxygen consumption (MVO(2)) and CE were determined in isolated perfused hearts; mitochondrial function was determined in permeabilized cardiac fibers and mitochondrial proteomics by liquid chromatography mass spectrometry. Pyruvate supported respiration and ATP synthesis were equivalently reduced by diabetes and genotype, with synergistic impairment in ATP synthesis in CIRKO-STZ. In contrast, fatty acid delivery and utilization was increased by diabetes irrespective of genotype, but not in non-diabetic CIRKO. Diabetes and genotype synergistically increased MVO(2) in CIRKO-STZ, leading to reduced CE. Irrespective of diabetes, genotype impaired ATP/O ratios in mitochondria exposed to palmitoyl carnitine, consistent with mitochondrial uncoupling. Proteomics revealed reduced content of fatty acid oxidation proteins in CIRKO mitochondria, which were induced by diabetes, whereas tricarboxylic acid cycle and oxidative phosphorylation proteins were reduced both in CIRKO mitochondria and by diabetes. CONCLUSIONS: Deficient insulin signaling and diabetes mediate distinct effects on cardiac mitochondria. Antecedent loss of insulin signaling markedly impairs CE when diabetes is induced, via mechanisms that may be secondary to mitochondrial uncoupling and increased FA utilization.
Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Coração/fisiopatologia , Receptor de Insulina/genética , Animais , Diabetes Mellitus Experimental/metabolismo , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/fisiopatologia , Técnicas de Inativação de Genes , Técnicas In Vitro , Insulina/fisiologia , Canais Iônicos/metabolismo , Masculino , Redes e Vias Metabólicas , Camundongos , Camundongos Knockout , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/fisiologia , Proteínas Mitocondriais/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Tamanho das Organelas , Oxirredução , Estresse Oxidativo , Consumo de Oxigênio , Proteoma/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptor de Insulina/deficiência , Proteína Desacopladora 3RESUMO
Capillary endothelial cells modulate myocardial growth and function during pathological stress, but it is unknown how and whether this contributes to the development of heart failure. We found that the endothelial cell transcription factor GATA2 is downregulated in human failing myocardium. Endothelial GATA2 knock-out (G2-EC-KO) mice develop heart failure and defective myocardial signal transduction during pressure overload, indicating that the GATA2 downregulation is maladaptive. Heart failure and perturbed signaling in G2-EC-KO mice could be induced by strong upregulation of two unknown, endothelial cell-derived long non-coding (lnc) RNAs (AK037972, AK038629, termed here GADLOR1 and 2). Mechanistically, the GADLOR1/2 lncRNAs transfer from endothelial cells to cardiomyocytes, where they block stress-induced signalling. Thereby, lncRNAs can contribute to disease as paracrine effectors of signal transduction and therefore might serve as therapeutic targets in the future.
RESUMO
Insulin and insulin-like growth factor 1 (IGF1) signaling is transduced by insulin receptor substrate 1 (IRS1) and IRS2. To elucidate physiological and redundant roles of insulin and IGF1 signaling in adult hearts, we generated mice with inducible cardiomyocyte-specific deletion of insulin and IGF1 receptors or IRS1 and IRS2. Both models developed dilated cardiomyopathy, and most mice died by 8 weeks post-gene deletion. Heart failure was characterized by cardiomyocyte loss and disarray, increased proapoptotic signaling, and increased autophagy. Suppression of autophagy by activating mTOR signaling did not prevent heart failure. Transcriptional profiling revealed reduced serum response factor (SRF) transcriptional activity and decreased mRNA levels of genes encoding sarcomere and gap junction proteins as early as 3 days post-gene deletion, in concert with ultrastructural evidence of sarcomere disruption and intercalated discs within 1 week after gene deletion. These data confirm conserved roles for constitutive insulin and IGF1 signaling in suppressing autophagic and apoptotic signaling in the adult heart. The present study also identifies an unexpected role for insulin and IGF1 signaling in regulating an SRF-mediated transcriptional program, which maintains expression of genes encoding proteins that support sarcomere integrity in the adult heart, reduction of which results in rapid development of heart failure.