Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.911
Filtrar
1.
Int J Mol Sci ; 22(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200497

RESUMO

Left ventricular (LV) heart failure (HF) is a significant and increasing cause of death worldwide. HF is characterized by myocardial remodeling and excessive fibrosis. Transcriptional co-activator Yes-associated protein (Yap), the downstream effector of HIPPO signaling pathway, is an essential factor in cardiomyocyte survival; however, its status in human LV HF is not entirely elucidated. Here, we report that Yap is elevated in LV tissue of patients with HF, and is associated with down-regulation of its upstream inhibitor HIPPO component large tumor suppressor 1 (LATS1) activation as well as upregulation of the fibrosis marker connective tissue growth factor (CTGF). Applying the established profibrotic combined stress of TGFß and hypoxia to human ventricular cardiac fibroblasts in vitro increased Yap protein levels, down-regulated LATS1 activation, increased cell proliferation and collagen I production, and decreased ribosomal protein S6 and S6 kinase phosphorylation, a hallmark of mTOR activation, without any significant effect on mTOR and raptor protein expression or phosphorylation of mTOR or 4E-binding protein 1 (4EBP1), a downstream effector of mTOR pathway. As previously reported in various cell types, TGFß/hypoxia also enhanced cardiac fibroblast Akt and ERK1/2 phosphorylation, which was similar to our observation in LV tissues from HF patients. Further, depletion of Yap reduced TGFß/hypoxia-induced cardiac fibroblast proliferation and Akt phosphorylation at Ser 473 and Thr308, without any significant effect on TGFß/hypoxia-induced ERK1/2 activation or reduction in S6 and S6 kinase activities. Taken together, these data demonstrate that Yap is a mediator that promotes human cardiac fibroblast proliferation and suggest its possible contribution to remodeling of the LV, opening the door to further studies to decipher the cell-specific roles of Yap signaling in human HF.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proliferação de Células , Insuficiência Cardíaca/patologia , Miofibroblastos/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Estudos de Casos e Controles , Células Cultivadas , Feminino , Insuficiência Cardíaca/metabolismo , Humanos , Masculino , Miofibroblastos/metabolismo , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Fatores de Transcrição/genética , Ativação Transcricional
2.
Int J Mol Sci ; 22(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207723

RESUMO

A hypofibrotic phenotype has been observed in cardiac fibroblasts (CFs) isolated from a volume overload heart failure model, aortocaval fistula (ACF). This paradoxical phenotype results in decreased ECM synthesis despite increased TGF-ß presence. Since ACF results in decreased tissue stiffness relative to control (sham) hearts, this study investigates whether the effects of substrate stiffness could account for the observed hypofibrotic phenotype in CFs isolated from ACF. CFs isolated from ACF and sham hearts were plated on polyacrylamide gels of a range of stiffness (2 kPa to 50 kPa). Markers related to cytoskeletal and fibrotic proteins were measured. Aspects of the hypofibrotic phenotype observed in ACF CFs were recapitulated by sham CFs on soft substrates. For instance, sham CFs on the softest gels compared to ACF CFs on the stiffest gels results in similar CTGF (0.80 vs. 0.76) and transgelin (0.44 vs. 0.57) mRNA expression. The changes due to stiffness may be explained by the observed decreased nuclear translocation of transcriptional regulators, MRTF-A and YAP. ACF CFs appear to have a mechanical memory of a softer environment, supported by a hypofibrotic phenotype overall compared to sham with less YAP detected in the nucleus, and less CTGF and transgelin on all stiffnesses.


Assuntos
Fibroblastos/metabolismo , Regulação da Expressão Gênica , Insuficiência Cardíaca/metabolismo , Miocárdio/metabolismo , Estresse Mecânico , Animais , Fibroblastos/patologia , Fibrose , Insuficiência Cardíaca/patologia , Masculino , Miocárdio/patologia , Ratos , Ratos Sprague-Dawley
3.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070765

RESUMO

Heart failure (HF) affects up to over 20% of patients with type 2 diabetes (T2DM), even more in the elderly. Although, in T2DM, both hyperglycemia and the proinflammatory status induced by insulin resistance are crucial in cardiac function impairment, SGLT2i cardioprotective mechanisms against HF are several. In particular, these beneficial effects seem attributable to the significant reduction of intracellular sodium levels, well-known to exert a cardioprotective role in the prevention of oxidative stress and consequent cardiomyocyte death. From a molecular perspective, patients' exposure to gliflozins' treatment mimics nutrient and oxygen deprivation, with consequent autophagy stimulation. This allows to maintain the cellular homeostasis through different degradative pathways. Thus, since their introduction in the clinical practice, the hypotheses on SGLT2i mechanisms of action have changed: from simple glycosuric drugs, with consequent glucose lowering, erythropoiesis enhancing and ketogenesis stimulating, to intracellular sodium-lowering molecules. This provides their consequent cardioprotective effect, which justifies its significant reduction in CV events, especially in populations at higher risk. Finally, the updated clinical evidence of SGLT2i benefits on HF was summarized. Thus, this review aimed to analyze the cardioprotective mechanisms of sodium glucose transporter 2 inhibitors (SGLT2i) in patients with HF, as well as their clinical impact on cardiovascular events.


Assuntos
Cardiotônicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Resistência à Insulina/genética , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Transportador 2 de Glucose-Sódio/genética , Idoso , Autofagia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/mortalidade , Diabetes Mellitus Tipo 2/patologia , Eritropoese/efeitos dos fármacos , Eritropoese/genética , Regulação da Expressão Gênica , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/patologia , Hospitalização/estatística & dados numéricos , Humanos , Sódio/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo , Análise de Sobrevida
4.
Nat Commun ; 12(1): 2529, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33953175

RESUMO

In the past decade, many long noncoding RNAs (lncRNAs) have been identified and their in vitro functions defined, although in some cases their functions in vivo remain less clear. Moreover, unlike nuclear lncRNAs, the roles of cytoplasmic lncRNAs are less defined. Here, using a gene trapping approach in mouse embryonic stem cells, we identify Caren (short for cardiomyocyte-enriched noncoding transcript), a cytoplasmic lncRNA abundantly expressed in cardiomyocytes. Caren maintains cardiac function under pathological stress by inactivating the ataxia telangiectasia mutated (ATM)-DNA damage response (DDR) pathway and activating mitochondrial bioenergetics. The presence of Caren transcripts does not alter expression of nearby (cis) genes but rather decreases translation of an mRNA transcribed from a distant gene encoding histidine triad nucleotide-binding protein 1 (Hint1), which activates the ATM-DDR pathway and reduces mitochondrial respiratory capacity in cardiomyocytes. Therefore, the cytoplasmic lncRNA Caren functions in cardioprotection by regulating translation of a distant gene and maintaining cardiomyocyte homeostasis.


Assuntos
Dano ao DNA/fisiologia , Insuficiência Cardíaca/metabolismo , Biogênese de Organelas , RNA Longo não Codificante/metabolismo , Animais , Núcleo Celular , Metabolismo Energético , Fibroblastos , Insuficiência Cardíaca/patologia , Homeostase , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Mitocôndrias/metabolismo , Células-Tronco Embrionárias Murinas , Miócitos Cardíacos/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , RNA Longo não Codificante/genética , RNA Mensageiro/metabolismo
5.
Nat Commun ; 12(1): 3155, 2021 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-34039977

RESUMO

Compact cardiomyocytes that make up the ventricular wall of the adult heart represent an important therapeutic target population for modeling and treating cardiovascular diseases. Here, we established a differentiation strategy that promotes the specification, proliferation and maturation of compact ventricular cardiomyocytes from human pluripotent stem cells (hPSCs). The cardiomyocytes generated under these conditions display the ability to use fatty acids as an energy source, a high mitochondrial mass, well-defined sarcomere structures and enhanced contraction force. These ventricular cells undergo metabolic changes indicative of those associated with heart failure when challenged in vitro with pathological stimuli and were found to generate grafts consisting of more mature cells than those derived from immature cardiomyocytes following transplantation into infarcted rat hearts. hPSC-derived atrial cardiomyocytes also responded to the maturation cues identified in this study, indicating that the approach is broadly applicable to different subtypes of the heart. Collectively, these findings highlight the power of recapitulating key aspects of embryonic and postnatal development for generating therapeutically relevant cell types from hPSCs.


Assuntos
Técnicas de Cultura de Células/métodos , Insuficiência Cardíaca/terapia , Infarto do Miocárdio/terapia , Miócitos Cardíacos/transplante , Células-Tronco Pluripotentes/fisiologia , Animais , Diferenciação Celular , Linhagem Celular , Proliferação de Células , Modelos Animais de Doenças , Embrião de Mamíferos , Desenvolvimento Embrionário/fisiologia , Átrios do Coração/citologia , Átrios do Coração/embriologia , Insuficiência Cardíaca/patologia , Ventrículos do Coração/citologia , Ventrículos do Coração/embriologia , Ventrículos do Coração/patologia , Humanos , Infarto do Miocárdio/complicações , Infarto do Miocárdio/patologia , Miócitos Cardíacos/fisiologia , Ratos
6.
Medicine (Baltimore) ; 100(16): e25621, 2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33879733

RESUMO

ABSTRACT: This study aimed to investigate the effects of the basic treatment for heart failure and sequential treatment with rh-brain natriuretic peptide (rhBNP) alone or the combination of rhBNP and sacubitril/valsartan. Cardiac structure, pulmonary artery pressure, inflammation and oxidative stress in patients with acute heart failure were evaluated.Three hundred patients with acute heart failure were included. According to the random number table method, the patients were divided into 3 groups of 100 patients per group: the standard treatment group (treated with an angiotensin-converting enzyme inhibitor, ß receptor blocker, and corticosteroid antagonist), rhBNP group (basic treatment combined with rhBNP) and sequential treatment group (basic treatment for heart failure combined with rhBNP followed by sacubitril/valsartan). The changes in NT-probrain natriuretic peptide (BNP) levels, cardiac troponin T (cTnT) levels, cardiac structure, pulmonary artery pressure, and the levels inflammatory factors and oxidative stress factors were compared among the 3 groups at 1, 4, 12, and 36 weeks after treatment.The sequential treatment group displayed superior outcomes than the standard treatment group and the rhBNP group in terms of left atrium diameter, left ventricular end diastolic volume, left ventricular ejection fraction, pulmonary artery pressure, NT-proBNP levels, and cTnT levels, which respond to damage to the heart structure and myocardium. This result may be related to the decreased levels of inflammatory factors and the correction of oxidative stress imbalance.Sacubitril/valsartan significantly reduce the serum levels of inflammatory factors in patients with acute heart failure while decreasing the levels of oxidizing factors and increasing the levels of antioxidant factors. These changes may be one of the explanations for the better cardiac structure and better pulmonary artery pressure observed in the sequential treatment group.


Assuntos
Aminobutiratos/administração & dosagem , Antagonistas de Receptores de Angiotensina/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Peptídeo Natriurético Encefálico/administração & dosagem , Tetrazóis/administração & dosagem , Doença Aguda , Antagonistas Adrenérgicos beta/administração & dosagem , Idoso , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Pressão Arterial/efeitos dos fármacos , Biomarcadores/sangue , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Antagonistas de Hormônios/administração & dosagem , Humanos , Inflamação , Mediadores da Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Artéria Pulmonar/fisiopatologia , Volume Sistólico/efeitos dos fármacos , Resultado do Tratamento , Troponina T/sangue
7.
Int J Mol Sci ; 22(8)2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33923401

RESUMO

Heart failure (HF) and atrial fibrillation (AF) are two major life-threatening diseases worldwide. Causes and mechanisms are incompletely understood, yet current therapies are unable to stop disease progression. In this review, we focus on the contribution of the transcriptional modulator, Jun dimerization protein 2 (JDP2), and on HF and AF development. In recent years, JDP2 has been identified as a potential prognostic marker for HF development after myocardial infarction. This close correlation to the disease development suggests that JDP2 may be involved in initiation and progression of HF as well as in cardiac dysfunction. Although no studies have been done in humans yet, studies on genetically modified mice impressively show involvement of JDP2 in HF and AF, making it an interesting therapeutic target.


Assuntos
Fibrilação Atrial/metabolismo , Insuficiência Cardíaca/metabolismo , Proteínas Repressoras/genética , Animais , Fibrilação Atrial/genética , Fibrilação Atrial/patologia , Biomarcadores/metabolismo , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Humanos , Proteínas Repressoras/metabolismo , Remodelação Ventricular
8.
FASEB J ; 35(5): e21512, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33811692

RESUMO

Vascular rarefaction due to impaired angiogenesis is associated with contractile dysfunction and the transition from compensation to decompensation and heart failure. The regulatory mechanism controlling vascular rarefaction during the transition remains elusive. Increased expression of a nuclear RNA-binding protein CUGBP Elav-like family member 1 (CELF1) in the adult heart is associated with the transition from compensated hypertrophy to decompensated heart failure. Elevated CELF1 level resulted in degradation of the major cardiac gap junction protein, connexin 43, in dilated cardiomyopathy (DCM), the most common cause of heart failure. In the present study, we investigated the role of increased CELF1 expression in causing vascular rarefaction in DCM. CELF1 overexpression (CELF1-OE) in cardiomyocytes resulted in reduced capillary density. CELF1-OE mice administered hypoxyprobe showed immunoreactivity and increased mRNA levels of HIF1α, Glut-1, and Pdk-1, which suggested the association of a reduced capillary density-induced hypoxic condition with CELF1 overexpression. Vegfa mRNA level was downregulated in mouse hearts exhibiting DCM, including CELF1-OE and infarcted hearts. Vegfa mRNA level was also downregulated to a similar extent in cardiomyocytes isolated from infarcted hearts by Langendorff preparation, which suggested cardiomyocyte-derived Vegfa expression mediated by CELF1. Cardiomyocyte-specific depletion of CELF1 preserved the capillary density and Vegfa mRNA level in infarcted mouse hearts. Also, CELF1 bound to Vegfa mRNA and regulated Vegfa mRNA stability via the 3' untranslated region. These results suggest that elevated CELF1 level has dual effects on impairing the functions of cardiomyocytes and microvasculature in DCM.


Assuntos
Proteínas CELF1/metabolismo , Insuficiência Cardíaca/patologia , Microvasos/patologia , Proteólise , Estabilidade de RNA , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Proteínas CELF1/genética , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microvasos/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética
9.
Diabetes Res Clin Pract ; 175: 108796, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33845051

RESUMO

Sodium-glucose transporter-2 inhibitors (SGLT2i), originally launched as glucose-lowering drugs, have been studied in large cardiovascular outcome trials to ascertain safety. Surprisingly, these compounds reduced the risk of cardiovascular events (cardiovascular death, non-fatal myocardial and non-fatal stroke) and total mortality. The mechanisms behind this benefit are only partly understood, but a major contributor is the reduction of heart failure hospitalisations, evident already within weeks after the initiation of the SGLT2i. SGLT2 inhibition increases urinary glucose excretion, thereby improving glycaemic control in an insulin-independent manner. Moreover, SGLT2i potentially impact the cardiovascular system both indirectly via weight loss and blood pressure lowering and directly through osmotic diuresis and increased sodium excretion and presumably by improving myocardial energetics. The aim of this review is to summarise evidence from all major outcome trials investigating SGLT2i in patients with diabetes, as well as recent evidence from trials in heart failure patients without glucose perturbations, which pave the way for novel treatment of large groups of patients. The results of these studies have been taken into account in recently issued guidelines for the management of diabetes and cardiovascular disease. An important task for diabetologists, cardiologists and general practitioners is to incorporate them into clinical practice to the benefit of many patients.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Doenças Cardiovasculares/patologia , Insuficiência Cardíaca/patologia , Humanos , Prognóstico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
10.
J Cardiothorac Surg ; 16(1): 98, 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33879206

RESUMO

BACKGROUND: Heart failure (HF) is one of the leading causes of mortality and morbidity. The PARACHUTE device is designed to partition for left ventricular (LV) apical aneurysm post extensive anterior myocardial infarction (MI). However, the long-term prognosis of the PARACHUTE device post-implantation is unclear. METHODS: From November 2015 to April 2017, six subjects with New York Heart Association Classes II, III and IV ischemic HF, LV ejection fraction between (LVEF) 15 and 40%; and LV anterior apical aneurysm were enrolled in our center. The cumulative event rates for MI, hospitalization, and mortality were documented. Further assessment of LVEF, LV end-diastolic diameter (LVEDD), and estimated pulmonary artery pressure were determined by echocardiography core laboratory. For quantitative data comparison, paired t-test was employed. RESULTS: Device implantation was successful in all six enrolled subjects, and acute device association adverse events were not observed. At 4.6 ± 1.7 years follow-up, major adverse cardiac events (MACEs) were found in 50% patients, and the survival rate was 86.7%. We observed that the LVEF was significantly elevated after deployment (46.00 ± 6.00% vs. 35.83 ± 1.47%, P = 0.009). Besides, the LVEDD elevated after MI (51.17 ± 3.71 vs. 62.83 ± 3.25, P < 0.001) was revealed, but the device sustained preserved LVEDD after implantation. CONCLUSION: The PARACHUTE device is an alternative therapy for patients with severe LV maladaptive remodeling. However, the device seems to increase the HF ratio. TRIAL REGISTRATION: NCT02240940.


Assuntos
Insuficiência Cardíaca/cirurgia , Coração Auxiliar , Infarto do Miocárdio/cirurgia , Implantação de Prótese/instrumentação , Adulto , Idoso , China , Feminino , Seguimentos , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Prognóstico , Estudos Retrospectivos , Volume Sistólico , Função Ventricular Esquerda , Remodelação Ventricular
11.
Int J Mol Sci ; 22(4)2021 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-33668422

RESUMO

BACKGROUND: Pathological activation of cardiac fibroblasts is a key step in development and progression of cardiac fibrosis and heart failure. This process has been associated with enhanced autophagocytosis, but molecular mechanisms remain largely unknown. METHODS AND RESULTS: Immunohistochemical analysis of endomyocardial biopsies showed increased activation of autophagy in fibrotic hearts of patients with inflammatory cardiomyopathy. In vitro experiments using mouse and human cardiac fibroblasts confirmed that blockade of autophagy with Bafilomycin A1 inhibited fibroblast-to-myofibroblast transition induced by transforming growth factor (TGF)-ß. Next, we observed that cardiac fibroblasts obtained from mice overexpressing transcription factor Fos-related antigen 2 (Fosl-2tg) expressed elevated protein levels of autophagy markers: the lipid modified form of microtubule-associated protein 1A/1B-light chain 3B (LC3BII), Beclin-1 and autophagy related 5 (Atg5). In complementary experiments, silencing of Fosl-2 with antisense GapmeR oligonucleotides suppressed production of type I collagen, myofibroblast marker alpha smooth muscle actin and autophagy marker Beclin-1 in cardiac fibroblasts. On the other hand, silencing of either LC3B or Beclin-1 reduced Fosl-2 levels in TGF-ß-activated, but not in unstimulated cells. Using a cardiac hypertrophy model induced by continuous infusion of angiotensin II with osmotic minipumps, we confirmed that mice lacking either Fosl-2 (Ccl19CreFosl2flox/flox) or Atg5 (Ccl19CreAtg5flox/flox) in stromal cells were protected from cardiac fibrosis. CONCLUSION: Our findings demonstrate that Fosl-2 regulates autophagocytosis and the TGF-ß-Fosl-2-autophagy axis controls differentiation of cardiac fibroblasts. These data provide a new insight for the development of pharmaceutical targets in cardiac fibrosis.


Assuntos
Fibroblastos/metabolismo , Antígeno 2 Relacionado a Fos/metabolismo , Regulação da Expressão Gênica , Insuficiência Cardíaca/metabolismo , Miocárdio/metabolismo , Fator de Transcrição AP-1/metabolismo , Idoso , Animais , Feminino , Fibroblastos/patologia , Fibrose , Antígeno 2 Relacionado a Fos/genética , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Miocárdio/patologia , Fator de Transcrição AP-1/genética
12.
Nat Commun ; 12(1): 1483, 2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33674611

RESUMO

Acute myocardial infarction is a common condition responsible for heart failure and sudden death. Here, we show that following acute myocardial infarction in mice, CD8+ T lymphocytes are recruited and activated in the ischemic heart tissue and release Granzyme B, leading to cardiomyocyte apoptosis, adverse ventricular remodeling and deterioration of myocardial function. Depletion of CD8+ T lymphocytes decreases apoptosis within the ischemic myocardium, hampers inflammatory response, limits myocardial injury and improves heart function. These effects are recapitulated in mice with Granzyme B-deficient CD8+ T cells. The protective effect of CD8 depletion on heart function is confirmed by using a model of ischemia/reperfusion in pigs. Finally, we reveal that elevated circulating levels of GRANZYME B in patients with acute myocardial infarction predict increased risk of death at 1-year follow-up. Our work unravels a deleterious role of CD8+ T lymphocytes following acute ischemia, and suggests potential therapeutic strategies targeting pathogenic CD8+ T lymphocytes in the setting of acute myocardial infarction.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Granzimas/genética , Granzimas/metabolismo , Coração/fisiopatologia , Remodelação Ventricular/fisiologia , Animais , Apoptose , Linfócitos T CD8-Positivos/patologia , Modelos Animais de Doenças , Feminino , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Proteínas de Homeodomínio/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infarto do Miocárdio/metabolismo , Miocárdio/patologia , Suínos , Transcriptoma
13.
Int J Cardiol ; 333: 219-225, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33737165

RESUMO

BACKGROUND: In adult cardiomyopathy (CM), diffuse myocardial fibrosis is associated with adverse clinical outcome. However, its relevance in pediatric patients remains relatively unknown. The study aimed to evaluate myocardial extracellular volume (ECV) reflecting diffuse myocardial fibrosis with cardiovascular magnetic resonance (CMR) T1 mapping, and to analyze correlations with clinical and functional data in children and adolescents with different CM phenotypes. METHODS: Patients with primary dilated (DCM), hypertrophic (HCM) or left ventricular non-compaction CM (LVNC) were prospectively enrolled and compared with healthy controls. Study participants underwent standardized CMR with modified Look-Locker Inversion recovery (MOLLI) T1 mapping. RESULTS: In total, 33 patients (median age 12.0 years; DCM: n = 10, HCM: n = 13; LVNC: n = 10) and 7 controls (14.5 years) were included. DCM: ECV was higher than in controls (38.1 ± 7.5% vs. 27.2 ± 3.6%; p = 0.014). Patients with elevated ECV were younger than those with normal values (p = 0.044). ECV correlated with N-terminal pro brain natriuretic peptide (r = 0.66, p = 0.038), left ventricular ejection fraction (r = -0.63, p = 0.053), and stroke volume of left (r = -0.75, p = 0.013) and right ventricle (r = -0.67, p = 0.033). During a median follow-up of 25.3 months, 3 patients underwent heart transplantation (HTx), and 2 were listed for HTx. All 5 patients had elevated ECV. HCM/LVNC: ECV was within normal range in HCM (25.5 ± 4.5%) and LVNC (29.6 ± 4.2), and was not related with clinical and/or functional parameters. CONCLUSIONS: Our results indicate an increased burden of diffuse myocardial fibrosis in relation with younger age in pediatric DCM. ECV was associated with clinical and biventricular functional markers of heart failure in DCM.


Assuntos
Cardiomiopatias , Cardiomiopatia Dilatada , Insuficiência Cardíaca , Adolescente , Adulto , Cardiomiopatias/patologia , Cardiomiopatia Dilatada/diagnóstico por imagem , Cardiomiopatia Dilatada/patologia , Estudos de Casos e Controles , Criança , Meios de Contraste , Fibrose , Insuficiência Cardíaca/patologia , Humanos , Imagem Cinética por Ressonância Magnética , Miocárdio/patologia , Valor Preditivo dos Testes , Volume Sistólico , Função Ventricular Esquerda
14.
Oxid Med Cell Longev ; 2021: 6643871, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33728024

RESUMO

Heart failure (HF) is a complex chronic clinical disease characterized by among others the damage of the mitochondrial network. The disruption of the mitochondrial quality control and the imbalance in fusion-fission processes lead to a lack of energy supply and, finally, to cell death. BGP-15 (O-[3-piperidino-2-hydroxy-1-propyl]-nicotinic acid amidoxime dihydrochloride) is an insulin sensitizer molecule and has a cytoprotective effect in a wide variety of experimental models. In our recent work, we aimed to clarify the mitochondrial protective effects of BGP-15 in a hypertension-induced heart failure model and "in vitro." Spontaneously hypertensive rats (SHRs) received BGP-15 or placebo for 18 weeks. BGP-15 treatment preserved the normal mitochondrial ultrastructure and enhanced the mitochondrial fusion. Neonatal rat cardiomyocytes (NRCMs) were stressed by hydrogen-peroxide. BGP-15 treatment inhibited the mitochondrial fission processes, promoted mitochondrial fusion, maintained the integrity of the mitochondrial genome, and moreover enhanced the de novo biogenesis of the mitochondria. As a result of these effects, BGP-15 treatment also supports the maintenance of mitochondrial function through the preservation of the mitochondrial structure during hydrogen peroxide-induced oxidative stress as well as in an "in vivo" heart failure model. It offers the possibility, which pharmacological modulation of mitochondrial quality control under oxidative stress could be a novel therapeutic approach in heart failure.


Assuntos
Insuficiência Cardíaca/patologia , Mitocôndrias Cardíacas/metabolismo , Estresse Oxidativo , Oximas/farmacologia , Piperidinas/farmacologia , Animais , Animais Recém-Nascidos , Técnicas de Cultura de Células , Citrato (si)-Sintase/metabolismo , DNA/metabolismo , Dano ao DNA , DNA Mitocondrial/genética , Dinaminas/metabolismo , Transporte de Elétrons/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Genoma Mitocondrial , Insuficiência Cardíaca/etiologia , Hipertensão/complicações , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/ultraestrutura , Dinâmica Mitocondrial , Proteínas Mitocondriais/metabolismo , Miocárdio/patologia , Miocárdio/ultraestrutura , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/ultraestrutura , Peptídeo Natriurético Encefálico/metabolismo , Biogênese de Organelas , Estresse Oxidativo/efeitos dos fármacos , Oximas/administração & dosagem , Oximas/química , Consumo de Oxigênio/efeitos dos fármacos , Piperidinas/administração & dosagem , Piperidinas/química , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
15.
Mol Med Rep ; 23(5)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33760172

RESUMO

Sepsis is a life­threatening organ dysfunction caused by a dysregulated host response to infection, and is a leading cause of mortality worldwide. Myocardial dysfunction is associated with poor prognosis in patients with sepsis and contributes to a high risk of mortality. However, the pathophysiological mechanisms underlying sepsis­induced myocardial dysfunction are not completely understood. The aim of the present study was to investigate the role of toll­like receptor 4 (TLR4)/c­Jun N­terminal kinase (JNK) signaling in pro­inflammatory cytokine expression and cardiac dysfunction during lipopolysaccharide (LPS)­induced sepsis in mice. C57BL/6 mice were pretreated with TAK­242 or saline for 1 h and then subjected to LPS (12 mg/kg, intraperitoneal) treatment. Cardiac function was assessed using an echocardiogram. The morphological changes of the myocardium were examined by hematoxylin and eosin staining and transmission electron microscopy. The serum protein levels of cardiac troponin I (cTnI) and tumor necrosis factor­α (TNF­α) were determined by an enzyme­linked immunosorbent assay (ELISA). The TLR4 and JNK mRNA levels were analyzed via reverse transcription­quantitative PCR. TLR4, JNK and phosphorylated­JNK protein levels were measured by western blotting. In response to LPS, the activation of TLR4 and JNK in the myocardium was upregulated. There were significant increases in the serum levels of TNF­α and cTnI, as well as histopathological changes in the myocardium and suppressed cardiac function, following LPS stimulation. Inhibition of TLR4 activation using TAK­242 led to a decrease in the activation of JNK and reduced the protein expression of TNF­α in plasma, and alleviated histological myocardial injury and improved cardiac function during sepsis in mice. The present data suggested that the TLR4/JNK signaling pathway played a critical role in regulating the production of pro­inflammatory cytokines and myocardial dysfunction induced by LPS.


Assuntos
Insuficiência Cardíaca/genética , Sistema de Sinalização das MAP Quinases/genética , Sepse/genética , Receptor 4 Toll-Like/genética , Animais , Apoptose/genética , Citocinas/genética , Modelos Animais de Doenças , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/patologia , Humanos , Interleucina-6/genética , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Lipopolissacarídeos/toxicidade , Camundongos , Miocárdio/patologia , NF-kappa B/genética , Fosforilação/genética , Sepse/induzido quimicamente , Sepse/complicações , Sepse/patologia , Troponina I/genética , Fator de Necrose Tumoral alfa/genética
16.
J Med Ultrason (2001) ; 48(2): 225-234, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33768355

RESUMO

PURPOSE: Ascites can cause compression of the inferior vena cava (IVC), leading to increased renal venous pressure and renal congestion. Previously, the left renal vein diameter in liver cirrhosis patients with ascites was measured using computed tomography, showing that enlargement of the left renal vein diameter affects the prognosis. Herein, the diameter and flow velocity of the renal veins were measured using ultrasonography. METHODS: Abdominal ultrasonography was performed on 186 patients. The patients were divided into four groups: normal liver (n = 102), liver cirrhosis (LC) without ascites (n = 37), LC with ascites (n = 30), and congestive liver (n = 17). Ultrasonographic measurements for diameter and flow velocity of the IVC, left renal vein main trunk, and segmental renal vein were performed. RESULTS: The left renal vein diameter increased in the following order: normal liver, LC, LC with ascites, and congestive liver groups (P < 0.001). IVC flow velocity was lower and left renal vein diameter was larger in the congestive liver and LC with ascites groups. These results suggest that the two groups have different pathological conditions, but the mechanism of renal congestion is similar. In patients with LC, IVC compression due to ascites might cause blood stagnation and renal congestion. CONCLUSION: The left renal vein and IVC can be measured using ultrasonography. It might help in furthering our understanding of the pathophysiology of renal congestion in these patients.


Assuntos
Insuficiência Cardíaca/complicações , Cirrose Hepática/complicações , Veias Renais/diagnóstico por imagem , Veias Renais/patologia , Ultrassonografia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Ascite/diagnóstico por imagem , Ascite/patologia , Estudos Transversais , Feminino , Insuficiência Cardíaca/patologia , Humanos , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade
17.
Int J Mol Sci ; 22(4)2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33578969

RESUMO

Histone acetylation by epigenetic regulators has been shown to activate the transcription of hypertrophic response genes, which subsequently leads to the development and progression of heart failure. However, nothing is known about the acetylation of the histone tail and globular domains in left ventricular hypertrophy or in heart failure. The acetylation of H3K9 on the promoter of the hypertrophic response gene was significantly increased in the left ventricular hypertrophy stage, whereas the acetylation of H3K122 did not increase in the left ventricular hypertrophy stage but did significantly increase in the heart failure stage. Interestingly, the interaction between the chromatin remodeling factor BRG1 and p300 was significantly increased in the heart failure stage, but not in the left ventricular hypertrophy stage. This study demonstrates that stage-specific acetylation of the histone tail and globular domains occurs during the development and progression of heart failure, providing novel insights into the epigenetic regulatory mechanism governing transcriptional activity in these processes.


Assuntos
Insuficiência Cardíaca/metabolismo , Histonas/metabolismo , Acetilação , Animais , Técnicas de Cultura de Células , DNA Helicases/metabolismo , Proteína p300 Associada a E1A/metabolismo , Insuficiência Cardíaca/patologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos Endogâmicos Dahl , Ratos Sprague-Dawley , Fatores de Transcrição/metabolismo
18.
Am J Physiol Heart Circ Physiol ; 320(4): H1634-H1645, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33635162

RESUMO

Wnt/ß-catenin signaling plays a key role in pathological cardiac remodeling in adults. The identification of a tissue-specific Wnt/ß-catenin interaction factor may provide a tissue-specific clinical targeting strategy. Drosophila Pygo encodes the core interaction factor of Wnt/ß-catenin. Two Pygo homologs (Pygo1 and Pygo2) have been identified in mammals. Different from the ubiquitous expression profile of Pygo2, Pygo1 is enriched in cardiac tissue. However, the role of Pygo1 in mammalian cardiac disease is yet to be elucidated. In this study, we found that Pygo1 was upregulated in human cardiac tissues with pathological hypertrophy. Cardiac-specific overexpression of Pygo1 in mice spontaneously led to cardiac hypertrophy accompanied by declined cardiac function, increased heart weight/body weight and heart weight/tibial length ratios, and increased cell size. The canonical ß-catenin/T-cell transcription factor 4 (TCF4) complex was abundant in Pygo1-overexpressing transgenic (Pygo1-TG) cardiac tissue, and the downstream genes of Wnt signaling, that is, Axin2, Ephb3, and c-Myc, were upregulated. A tail vein injection of ß-catenin inhibitor effectively rescued the phenotype of cardiac failure and pathological myocardial remodeling in Pygo1-TG mice. Furthermore, in vivo downregulated pygo1 during cardiac hypertrophic condition antagonized agonist-induced cardiac hypertrophy. Therefore, our study is the first to present in vivo evidence demonstrating that Pygo1 regulates pathological cardiac hypertrophy in a canonical Wnt/ß-catenin-dependent manner, which may provide new clues for tissue-specific clinical treatment via targeting this pathway.NEW & NOTEWORTHY In this study, we found that Pygo1 is associated with human pathological hypertrophy. Cardiac-specific overexpression of Pygo1 in mice spontaneously led to cardiac hypertrophy. Meanwhile, cardiac function was improved when expression of Pygo1 was interfered in hypertrophy-model mice. Our study is the first to present in vivo evidence demonstrating that Pygo1 regulates pathological cardiac hypertrophy in a canonical Wnt/ß-catenin-dependent manner, which may provide new clues for a tissue-specific clinical treatment targeting this pathway.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Insuficiência Cardíaca/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , Miocárdio/metabolismo , Função Ventricular Esquerda , Remodelação Ventricular , Via de Sinalização Wnt , beta Catenina/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteína Axina/genética , Proteína Axina/metabolismo , Modelos Animais de Doenças , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/prevenção & controle , Hipertrofia Ventricular Esquerda/induzido quimicamente , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Hipertrofia Ventricular Esquerda/patologia , Isoproterenol , Masculino , Camundongos Transgênicos , Miocárdio/patologia , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Ratos , Receptor EphB3/genética , Receptor EphB3/metabolismo , Tiazolidinas/farmacologia , Fator de Transcrição 4/genética , Fator de Transcrição 4/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/antagonistas & inibidores
19.
Eur J Pharmacol ; 898: 173987, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33640405

RESUMO

Necroptosis is a programmed form of necrotic cell death. Necroptosis is regulated by the necroptosis-regulating proteins including receptor-interacting protein (RIP) 1, RIP3, and mixed lineage kinase domain-like (MLKL), the activities of which are modulated by the molecular chaperone heat-shock protein (Hsp) 90. Presently, to clarify the relationship between Hsp90 and necroptotic pathway proteins, RIP1, RIP3, and MLKL in the development of heart failure, we examined the effects of Hsp90 inhibitor treatment on the RIP1-RIP3-MLKL pathway in mice following transverse aortic constriction (TAC). In this study, TAC mice showed typical signs of heart failure at the 8th week after the operation. In the failing heart, the levels of these regulatory proteins and those of their phosphorylated forms were increased, suggesting that necroptosis contributed to the development of heart failure in the TAC mice. The increases in RIP1, RIP3, and MLKL after TAC were reversed by the administration of an Hsp90 inhibitor. Furthermore, the rise in the phosphorylation levels of these 3 proteins were attenuated by the Hsp90 inhibitor. Concomitantly, cardiac functions were preserved. We also found that exposure of cultured adult mouse cardiomyocytes to the Hsp90 inhibitor attenuated necrotic cell death induced by tumor necrosis factor-α via suppression of RIP1, RIP3, and MLKL activation in in vitro experiments. Taken together, our findings suggest that inhibition of Hsp90 should have therapeutic effects by reducing the activation of RIP1-RIP3-MLKL pathway in the hypertrophied heart and thus could be a new therapeutic strategy for chronic heart failure.


Assuntos
Benzoquinonas/farmacologia , Proteínas Ativadoras de GTPase/metabolismo , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Insuficiência Cardíaca/tratamento farmacológico , Lactamas Macrocíclicas/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Proteínas Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Proteínas de Choque Térmico HSP90/metabolismo , Insuficiência Cardíaca/enzimologia , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Necroptose/efeitos dos fármacos , Fosforilação , Transdução de Sinais , Fatores de Tempo , Função Ventricular Esquerda/efeitos dos fármacos
20.
Am J Physiol Heart Circ Physiol ; 320(4): H1658-H1669, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33635163

RESUMO

The goal of this work was to investigate the role of t-tubule (TT) remodeling in abnormal Ca2+ cycling in ventricular myocytes of failing dog hearts. Heart failure (HF) was induced using rapid right ventricular pacing. Extensive changes in echocardiographic parameters, including left and right ventricular dilation and systolic dysfunction, diastolic dysfunction, elevated left ventricular filling pressures, and abnormal cardiac mechanics, indicated that severe HF developed. TT loss was extensive when measured as the density of total cell volume, derived from three-dimensional confocal image analysis, and significantly increased the distances in the cell interior to closest cell membrane. Changes in Ca2+ transients indicated increases in heterogeneity of Ca2+ release along the cell length. When critical properties of Ca2+ release variability were plotted as a function of TT organization, there was a complex, nonlinear relationship between impaired calcium release and decreasing TT organization below a certain threshold of TT organization leading to increased sensitivity in Ca2+ release below a TT density threshold of 1.5%. The loss of TTs was also associated with a greater incidence of triggered Ca2+ waves during rapid pacing. Finally, virtually all of these observations were replicated by acute detubulation by formamide treatment, indicating an important role of TT remodeling in impaired Ca2+ cycling. We conclude that TT remodeling itself is a major contributor to abnormal Ca2+ cycling in HF, reducing myocardial performance. The loss of TTs is also responsible for a greater incidence of triggered Ca2+ waves that may play a role in ventricular arrhythmias arising in HF.NEW & NOTEWORTHY Three-dimensional analysis of t-tubule density showed t-tubule disruption throughout the whole myocyte in failing dog ventricle. A double-linear relationship between Ca2+ release and t-tubule density displays a steeper slope at t-tubule densities below a threshold value (∼1.5%) above which there is little effect on Ca2+ release (T-tubule reserve). T-tubule loss increases incidence of triggered Ca2+ waves. Chemically induced t-tubule disruption suggests that t-tubule loss alone is a critical component of abnormal Ca2+ cycling in heart failure.


Assuntos
Sinalização do Cálcio , Cálcio/metabolismo , Insuficiência Cardíaca/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Estimulação Cardíaca Artificial , Modelos Animais de Doenças , Cães , Feminino , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Masculino , Miócitos Cardíacos/patologia , Função Ventricular Esquerda , Função Ventricular Direita , Pressão Ventricular
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...