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1.
Int J Mol Sci ; 22(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34360729

RESUMO

Mitochondria are considered to be important organelles in the cell and play a key role in the physiological function of the heart, as well as in the pathogenesis and development of various heart diseases. Under certain pathological conditions, such as cardiovascular diseases, stroke, traumatic brain injury, neurodegenerative diseases, muscular dystrophy, etc., mitochondrial permeability transition pore (mPTP) is formed and opened, which can lead to dysfunction of mitochondria and subsequently to cell death. This review summarizes the results of studies carried out by our group of the effect of astaxanthin (AST) on the functional state of rat heart mitochondria upon direct addition of AST to isolated mitochondria and upon chronic administration of AST under conditions of mPTP opening. It was shown that AST exerted a protective effect under all conditions. In addition, AST treatment was found to prevent isoproterenol-induced oxidative damage to mitochondria and increase mitochondrial efficiency. AST, a ketocarotenoid, may be a potential mitochondrial target in therapy for pathological conditions associated with oxidative damage and mitochondrial dysfunction, and may be a potential mitochondrial target in therapy for pathological conditions.


Assuntos
Sistemas de Liberação de Medicamentos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Mitocôndrias Cardíacas/metabolismo , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/patologia , Humanos , Isoproterenol/efeitos adversos , Isoproterenol/uso terapêutico , Mitocôndrias Cardíacas/patologia , Oxirredução/efeitos dos fármacos , Xantofilas/uso terapêutico
2.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445662

RESUMO

Acute myocardial infarction (MI) is associated with an intense inflammatory response that is critical for cardiac repair but is also involved in the pathogenesis of adverse cardiac remodeling, i.e., the set of size, geometry, and structure changes that represent the structural substrate for the development of post-MI heart failure. Deciphering the pathophysiological mechanisms underlying cardiac repair after MI is, therefore, critical to favorably regulate cardiac wound repair and to prevent development of heart failure. Catecholamines and estrogen play an active role in regulating the inflammatory response in the infarcted area. For example, stress-induced catecholamines alter recruitment and trafficking of leukocytes to the heart. Additionally, estrogen affects rate of cardiac rupture during the acute phase of MI, as well as infarct size and survival in animal models of MI. In this review, we will summarize the role of ß-adrenergic receptors and estrogen in cardiac repair after infarction in preclinical studies.


Assuntos
Estrogênios/metabolismo , Insuficiência Cardíaca/prevenção & controle , Infarto do Miocárdio/complicações , Receptores Adrenérgicos beta/metabolismo , Remodelação Ventricular , Animais , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Humanos
3.
PLoS One ; 16(8): e0256035, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34398893

RESUMO

BACKGROUND: Chloroquine was promoted as a COVID-19 therapeutic early in the pandemic. Most countries have since discontinued the use of chloroquine due to lack of evidence of any benefit and the risk of severe adverse events. The primary aim of this study was to examine if administering chloroquine during COVID-19 imposed an increased risk of ischemic heart injury or heart failure. METHODS: Medical records, laboratory findings, and electrocardiograms of patients with COVID-19 who were treated with 500 mg chloroquine phosphate daily and controls not treated with chloroquine were reviewed retrospectively. Controls were matched in age and severity of disease. RESULTS: We included 20 patients receiving chloroquine (500 mg twice daily) for an average of five days, and 40 controls. The groups were comparable regarding demographics and biochemical analyses including C-reactive protein, thrombocytes, and creatinine. There were no statistically significant differences in cardiac biomarkers or in electrocardiograms. Median troponin T was 10,8 ng/L in the study group and 17.9 ng/L in the control group, whereas median NT-proBNP was 399 ng/L in patients receiving chloroquine and 349 ng/L in the controls. CONCLUSIONS: We found no increased risk of ischemic heart injury or heart failure as a result of administering chloroquine. However, the use of chloroquine to treat COVID-19 outside of clinical trials is not recommended, considering the lack of evidence of its effectiveness, as well as the elevated risk of fatal arrythmias.


Assuntos
Antivirais/efeitos adversos , Biomarcadores/análise , Cloroquina/análogos & derivados , Insuficiência Cardíaca/etiologia , Traumatismos Cardíacos/etiologia , Idoso , Antivirais/uso terapêutico , Proteína C-Reativa/análise , COVID-19/tratamento farmacológico , COVID-19/patologia , COVID-19/virologia , Estudos de Casos e Controles , Cloroquina/efeitos adversos , Cloroquina/uso terapêutico , Creatinina/análise , Eletrocardiografia , Feminino , Insuficiência Cardíaca/metabolismo , Traumatismos Cardíacos/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/análise , Fragmentos de Peptídeos/análise , Estudos Retrospectivos , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença , Troponina T/análise
4.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281199

RESUMO

The current global prevalence of heart failure is estimated at 64.34 million cases, and it is expected to increase in the coming years, especially in countries with a medium-low sociodemographic index where the prevalence of risk factors is increasing alarmingly. Heart failure is associated with many comorbidities and among them, cancer has stood out as a contributor of death in these patients. This connection points out new challenges both in the context of the pathophysiological mechanisms involved, as well as in the quality of life of affected individuals. A hallmark of heart failure is chronic activation of the renin-angiotensin-aldosterone system, especially marked by a systemic increase in levels of angiotensin-II, a peptide with pleiotropic activities. Drugs that target the renin-angiotensin-aldosterone system have shown promising results both in the prevention of secondary cardiovascular events in myocardial infarction and heart failure, including a lower risk of certain cancers in these patients, as well as in current cancer therapies; therefore, understanding the mechanisms involved in this complex relationship will provide tools for a better diagnosis and treatment and to improve the prognosis and quality of life of people suffering from these two deadly diseases.


Assuntos
Isquemia Miocárdica/fisiopatologia , Neoplasias/fisiopatologia , Sistema Renina-Angiotensina/fisiologia , Aldosterona/metabolismo , Angiotensina II/metabolismo , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Infarto do Miocárdio/fisiopatologia , Isquemia Miocárdica/metabolismo , Neoplasias/metabolismo , Renina/metabolismo
5.
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
6.
Nat Commun ; 12(1): 4583, 2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-34321484

RESUMO

Voltage dependent anion channel 2 (VDAC2) is an outer mitochondrial membrane porin known to play a significant role in apoptosis and calcium signaling. Abnormalities in calcium homeostasis often leads to electrical and contractile dysfunction and can cause dilated cardiomyopathy and heart failure. However, the specific role of VDAC2 in intracellular calcium dynamics and cardiac function is not well understood. To elucidate the role of VDAC2 in calcium homeostasis, we generated a cardiac ventricular myocyte-specific developmental deletion of Vdac2 in mice. Our results indicate that loss of VDAC2 in the myocardium causes severe impairment in excitation-contraction coupling by altering both intracellular and mitochondrial calcium signaling. We also observed adverse cardiac remodeling which progressed to severe cardiomyopathy and death. Reintroduction of VDAC2 in 6-week-old knock-out mice partially rescued the cardiomyopathy phenotype. Activation of VDAC2 by efsevin increased cardiac contractile force in a mouse model of pressure-overload induced heart failure. In conclusion, our findings demonstrate that VDAC2 plays a crucial role in cardiac function by influencing cellular calcium signaling. Through this unique role in cellular calcium dynamics and excitation-contraction coupling VDAC2 emerges as a plausible therapeutic target for heart failure.


Assuntos
Cálcio/metabolismo , Cardiomiopatia Dilatada/metabolismo , Homeostase , Canal de Ânion 2 Dependente de Voltagem/genética , Canal de Ânion 2 Dependente de Voltagem/metabolismo , Animais , Apoptose , Sinalização do Cálcio , Cardiomiopatia Dilatada/mortalidade , Insuficiência Cardíaca/metabolismo , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Membranas Mitocondriais/metabolismo , Contração Miocárdica , Miócitos Cardíacos/metabolismo , Transcriptoma
7.
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
8.
Cardiovasc Res ; 117(10): 2161-2174, 2021 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-34114614

RESUMO

We review some of the important discoveries and advances made in basic and translational cardiac research in 2020. For example, in the field of myocardial infarction (MI), new aspects of autophagy and the importance of eosinophils were described. Novel approaches, such as a glycocalyx mimetic, were used to improve cardiac recovery following MI. The strategy of 3D bio-printing was shown to allow the fabrication of a chambered cardiac organoid. The benefit of combining tissue engineering with paracrine therapy to heal injured myocardium is discussed. We highlight the importance of cell-to-cell communication, in particular, the relevance of extracellular vesicles, such as exosomes, which transport proteins, lipids, non-coding RNAs, and mRNAs and actively contribute to angiogenesis and myocardial regeneration. In this rapidly growing field, new strategies were developed to stimulate the release of reparative exosomes in ischaemic myocardium. Single-cell sequencing technology is causing a revolution in the study of transcriptional expression at cellular resolution, revealing unanticipated heterogeneity within cardiomyocytes, pericytes and fibroblasts, and revealing a unique subpopulation of cardiac fibroblasts. Several studies demonstrated that exosome- and non-coding RNA-mediated approaches can enhance human induced pluripotent stem cell (iPSC) viability and differentiation into mature cardiomyocytes. Important details of the mitochondrial Ca2+ uniporter and its relevance were elucidated. Novel aspects of cancer therapeutic-induced cardiotoxicity were described, such as the novel circular RNA circITCH, which may lead to novel treatments. Finally, we provide some insights into the effects of SARS-CoV-2 on the heart.


Assuntos
Pesquisa Biomédica , Cardiologia , Proliferação de Células , Insuficiência Cardíaca/patologia , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/patologia , Regeneração , Animais , COVID-19/patologia , COVID-19/virologia , Comunicação Celular , Microambiente Celular , Exossomos/metabolismo , Exossomos/patologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/virologia , Fenótipo , RNA não Traduzido/metabolismo , SARS-CoV-2/patogenicidade
9.
Int J Mol Sci ; 22(11)2021 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-34067440

RESUMO

Myocardial infarction remains the most common cause of heart failure with adverse remodeling. MicroRNA (miR)155 is upregulated following myocardial infarction and represents a relevant regulatory factor for cardiac remodeling by engagement in cardiac inflammation, fibrosis and cardiomyocyte hypertrophy. Here, we investigated the role of miR155 in cardiac remodeling and dysfunction following myocardial infarction in a dyslipidemic mouse model. Myocardial infarction was induced in dyslipidemic apolipoprotein E-deficient (ApoE-/-) mice with and without additional miR155 knockout by ligation of the LAD. Four weeks later, echocardiography was performed to assess left ventricular (LV) dimensions and function, and mice were subsequently sacrificed for histological analysis. Echocardiography revealed no difference in LV ejection fractions, LV mass and LV volumes between ApoE-/- and ApoE-/-/miR155-/- mice. Histology confirmed comparable infarction size and unaltered neoangiogenesis in the myocardial scar. Notably, myofibroblast density was significantly decreased in ApoE-/-/miR155-/- mice compared to the control, but no difference was observed for total collagen deposition. Our findings reveal that genetic depletion of miR155 in a dyslipidemic mouse model of myocardial infarction does not reduce infarction size and consecutive heart failure but does decrease myofibroblast density in the post-ischemic scar.


Assuntos
MicroRNAs/genética , Infarto do Miocárdio/genética , Miofibroblastos/metabolismo , Função Ventricular Esquerda/genética , Animais , Modelos Animais de Doenças , Ecocardiografia/métodos , Fibrose/genética , Fibrose/metabolismo , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Ventrículos do Coração/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Volume Sistólico/genética , Remodelação Ventricular/genética
10.
Medicine (Baltimore) ; 100(22): e26180, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34087882

RESUMO

BACKGROUND: Heart failure (HF) is one of the common and critical disease, and often accompanied by increased level of serum bilirubin, but the role of an indicator of bilirubin to monitor the prognosis of patients with heart failure is still unclear, so we implemented the study to systematically evaluate the predictive value of bilirubin in HF. METHODS: A comprehensive search and systematic review will be conducted on electronic databases such as Medline, Cochrane Library, Embase, Web of Science, Cochrane Clinical Trials Database of study on the relationship between bilirubin and prognosis of HF patients. Review Manager software (version 5.3.5) and STATA 14 software (version 14.0) will be used for data analysis and synthesis. RESULTS: The results will systematically and comprehensively reveal the evidence on the predictive value of bilirubin in HF. CONCLUSION: The study will display the effect of bilirubin level on the prognosis of patients with heart failure, and help clinicians to pay more attention to the level of bilirubin in patients with HF, and can take certain treatment measures as earlier as possible. INPLASY REGISTRATION NUMBER: INPLASY202140116.


Assuntos
Bilirrubina/sangue , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos como Assunto , Gerenciamento de Dados , Feminino , Insuficiência Cardíaca/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico
11.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071350

RESUMO

The heart has a reduced capacity to generate sufficient energy when failing, resulting in an energy-starved condition with diminished functions. Studies have identified numerous changes in metabolic pathways in the failing heart that result in reduced oxidation of both glucose and fatty acid substrates, defects in mitochondrial functions and oxidative phosphorylation, and inefficient substrate utilization for the ATP that is produced. Recent early-phase clinical studies indicate that inhibitors of fatty acid oxidation and antioxidants that target the mitochondria may improve heart function during failure by increasing compensatory glucose oxidation. Adrenergic receptors (α1 and ß) are a key sympathetic nervous system regulator that controls cardiac function. ß-AR blockers are an established treatment for heart failure and α1A-AR agonists have potential therapeutic benefit. Besides regulating inotropy and chronotropy, α1- and ß-adrenergic receptors also regulate metabolic functions in the heart that underlie many cardiac benefits. This review will highlight recent studies that describe how adrenergic receptor-mediated metabolic pathways may be able to restore cardiac energetics to non-failing levels that may offer promising therapeutic strategies.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos beta/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacos , Animais , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Redes e Vias Metabólicas/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Sistema Nervoso Simpático/metabolismo , Sistema Nervoso Simpático/fisiopatologia
12.
Mol Cell Biochem ; 476(9): 3449-3460, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33974232

RESUMO

Heart failure is a syndrome with symptoms or signs caused by cardiac dysfunction. In clinic, four stages (A, B, C, and D) were used to describe heart failure progression. This study was aimed to explore plasma metabolomic and lipidomic profiles in different HF stages to identify potential biomarkers. Metabolomics and lipidomics were performed using plasma of heart failure patients at stages A (n = 49), B (n = 61), and C+D (n = 26). Analysis of Variance (ANOVA) was used for screening dysregulated molecules. Bioinformatics was used to retrieve perturbed metabolic pathways. Univariate and multivariate receiver operating characteristic curve (ROC) analyses were used for potential biomarker screening. Stage A showed significant difference to other stages, and 142 dysregulated lipids and 134 dysregulated metabolites were found belonging to several metabolic pathways. Several marker panels were proposed for the diagnosis of heart failure stage A versus stage B-D. Several molecules, including lysophosphatidylcholine 18:2, cholesteryl ester 18:1, alanine, choline, and Fructose, were found correlated with B-type natriuretic peptide or left ventricular ejection fractions. In summary, using untargeted metabolomic and lipidomic profiling, several dysregulated small molecules were successfully identified between HF stages A and B-D. These molecules would provide valuable information for further pathological researches and biomarker development.


Assuntos
Biomarcadores/sangue , Insuficiência Cardíaca/diagnóstico , Lipidômica/métodos , Lipídeos/sangue , Metaboloma , Idoso , Estudos de Casos e Controles , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC
13.
Folia Histochem Cytobiol ; 59(2): 108-113, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34003485

RESUMO

INTRODUCTION: Endothelial dysfunction is a critical part of heart failure (HF) pathophysiology. It is not clear, however, whether it is present at the similar level in the early and late HF stages. MATERIAL AND METHODS: von Willebrand factor (vWF) and its mRNA levels in biopsies of non-ischemic patients with HF secondary to dilated cardiomyopathy were studied. Consecutive patients with HF were divided into two groups: group A with disease duration ≤ 12 months (n = 59) and group B with disease duration > 12 months (n = 68). The immunoreactivity of the vWF was compared with autopsy sections of 19 control cases. Tissue vWF gene expression was analyzed at the mRNA level by RT-PCR. RESULTS: In the group A, there was lower vWF immunoreactivity in the coronary microvessels compared to the group B [1.5 (1.0-2.0) vs. 2.0 (1.5-2.4), P = 0.001]. In the control group, only weak vWF expression was observed. Protein expression was not accompanied by vWF mRNA whose levels were significantly higher in the Group A as compared to the Group B [14671 (4932-51561) vs. 3643 (185.3-9030.8), P = 0.005]. Protein vWF expression was inversely associated with its mRNA levels (r = -0.34, P = 0.04). CONCLUSIONS: High myocardial protein expression of vWF in patients with long-lasting HF symptoms may highlight the persistent nature of endothelial dysfunction in such a cohort of patients.


Assuntos
Endotélio Vascular/metabolismo , Insuficiência Cardíaca/metabolismo , Miocárdio/metabolismo , Fator de von Willebrand/metabolismo , Adulto , Vasos Coronários/metabolismo , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Masculino , Microvasos/metabolismo , Pessoa de Meia-Idade , Regulação para Cima
14.
Acta Physiol (Oxf) ; 232(3): e13691, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34022101

RESUMO

Ca2+ mishandling is a common feature in several cardiovascular diseases such as heart failure (HF). In many cases, impairment of key players in intracellular Ca2+ homeostasis has been identified as the underlying mechanism of cardiac dysfunction and cardiac arrhythmias associated with HF. In this review, we summarize primary novel findings related to Ca2+ mishandling in HF progression. HF research has increasingly focused on the identification of new targets and the contribution of their role in Ca2+ handling to the progression of the disease. Recent research studies have identified potential targets in three major emerging areas implicated in regulation of Ca2+ handling: the innate immune system, bone metabolism factors and post-translational modification of key proteins involved in regulation of Ca2+ handling. Here, we describe their possible contributions to the progression of HF.


Assuntos
Insuficiência Cardíaca , Miócitos Cardíacos , Arritmias Cardíacas/metabolismo , Cálcio/metabolismo , Insuficiência Cardíaca/metabolismo , Humanos , Miócitos Cardíacos/metabolismo , Processamento de Proteína Pós-Traducional , Retículo Sarcoplasmático/metabolismo
15.
Life Sci ; 278: 119565, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33965380

RESUMO

More than one hundred RNA modifications decorate the chemical and topological properties of these ribose nucleotides, thereby executing their biological functions through post-transcriptional regulation. In cardiovascular diseases, a wide range of RNA modifications including m6A (N6-adenosine methylation), m5C (5-methylcytidin), Nm (2'-O-ribose-methylation), Ψ (pseudouridine), m7G (N7-methylguanosine), and m1A (N1-adenosine methylation) have been found in tRNA, rRNA, mRNA and other noncoding RNA, which can function as a novel mechanism in metabolic syndrome, heart failure, coronary heart disease, and hypertension. In this review, we will summarize the current understanding of the regulatory roles and significance of several types of RNA modifications in CVDs (cardiovascular diseases) and the interplay between RNA modifications and noncoding RNA, epigenetics. Finally, we will focus on the potential therapeutic strategies by using RNA modifications.


Assuntos
Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/terapia , Regulação da Expressão Gênica , RNA/metabolismo , Adenosina/metabolismo , Animais , Aterosclerose/metabolismo , Doença das Coronárias/metabolismo , Epigênese Genética , Fibrose/metabolismo , Perfilação da Expressão Gênica , Insuficiência Cardíaca/metabolismo , Humanos , Hipertensão Pulmonar/metabolismo , Hipertrofia , Síndrome Metabólica/metabolismo , Metilação , Camundongos , Microcirculação , Miocárdio/metabolismo , Processamento Pós-Transcricional do RNA , RNA não Traduzido/metabolismo , Regeneração , Traumatismo por Reperfusão , Transcriptoma
16.
Adv Exp Med Biol ; 1269: 101-105, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33966202

RESUMO

The primary symptom in patients with chronic heart failure (CHF) is exercise intolerance. Previous studies have reported that reduced exercise tolerance in CHF can be explained not only by cardiac output (a central factor) but also by reduced skeletal muscle aerobic capacity (a peripheral factor). Although exercise training in CHF improves exercise tolerance, few studies have evaluated the effects of exercise training on each specific central and peripheral factor in CHF. The aim of this study was to investigate the central and peripheral aerobic functions in CHF and the effects of exercise training in CHF on cardiac output and skeletal muscle deoxygenation during exercise. We assessed peak oxygen uptake (VO2) during cardiopulmonary exercise testing, peak cardiac output (CO) using noninvasive hemodynamic monitoring, and muscle oxygen saturation (SmO2) using near-infrared spectroscopy (NIRS). Patients with CHF were trained for 12 weeks and performed ramp cycling exercise until exhaustion before and after the exercise training. Peak VO2, peak CO, and SmO2 changes from rest to peak exercise (ΔSmO2) were significantly lower in CHF than those in healthy subjects. As a result of exercise training, peak oxygen uptake in patients with CHF was improved and positively associated with change in ΔSmO2. In contrast, there was no change in peak cardiac output. The results of this study indicate that both cardiac and skeletal muscle functions in patients with CHF were lower than those in healthy subjects. Further, the results suggest that the improvement of exercise capacity in patients with CHF by exercise training was related to the improved utilization of oxygen (a peripheral factor) in skeletal muscle.


Assuntos
Insuficiência Cardíaca , Consumo de Oxigênio , Exercício Físico , Teste de Esforço , Tolerância ao Exercício , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/terapia , Humanos , Músculo Esquelético/metabolismo
17.
Nat Commun ; 12(1): 2725, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976166

RESUMO

Transthyretin amyloid cardiomyopathy, an often unrecognized cause of heart failure, is now treatable with a transthyretin stabilizer. It is therefore important to identify at-risk patients who can undergo targeted testing for earlier diagnosis and treatment, prior to the development of irreversible heart failure. Here we show that a random forest machine learning model can identify potential wild-type transthyretin amyloid cardiomyopathy using medical claims data. We derive a machine learning model in 1071 cases and 1071 non-amyloid heart failure controls and validate the model in three nationally representative cohorts (9412 cases, 9412 matched controls), and a large, single-center electronic health record-based cohort (261 cases, 39393 controls). We show that the machine learning model performs well in identifying patients with cardiac amyloidosis in the derivation cohort and all four validation cohorts, thereby providing a systematic framework to increase the suspicion of transthyretin cardiac amyloidosis in patients with heart failure.


Assuntos
Neuropatias Amiloides Familiares/metabolismo , Cardiomiopatias/metabolismo , Insuficiência Cardíaca/metabolismo , Aprendizado de Máquina , Pré-Albumina/metabolismo , Neuropatias Amiloides Familiares/genética , Cardiomiopatias/genética , Registros Eletrônicos de Saúde , Insuficiência Cardíaca/genética , Humanos , Pré-Albumina/genética
18.
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
19.
BMC Vet Res ; 17(1): 176, 2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33902566

RESUMO

BACKGROUND: Inflammation and oxidative stress can contribute to the development and progression of heart failure. This study aimed to investigate the association between inflammatory and oxidative stress markers in dogs with congestive heart failure (CHF). Associations between the disease severity marker N-terminal pro-B-type natriuretic peptide (NT-proBNP) and markers of inflammation and oxidative stress were also determined. RESULTS: Thirty-seven dogs with cardiovascular diseases (dilated cardiomyopathy, DCM (16 dogs), myxomatous mitral valve disease, MMVD (21 dogs)) and ten healthy dogs were included in this prospective study. The patients were further divided into groups with (26) and without CHF (11). We found a significantly higher serum concentration of C-reactive protein (P = 0.012), white blood cell (P = 0.001), neutrophil (P = 0.001) and monocyte counts (P = 0.001) in patients with CHF compared to control dogs. The concentration of tumor necrosis factor-alpha (TNF-α) was significantly higher in patients with CHF compared to patients without CHF (P = 0.030). No significant difference was found in most of the measured parameters between MMVD and DCM patients, except for glutathione peroxidase (GPX) and NT-proBNP. In patients with CHF, TNF-α correlated positively with malondialdehyde (P = 0.014, r = 0.474) and negatively with GPX (P = 0.026, r = - 0.453), and interleukin-6 correlated negatively with GPX (P = 0.046, r = - 0.412). NT-proBNP correlated positively with malondialdehyde (P = 0.011, r = 0.493). In patients without CHF none of the inflammatory and oxidative stress markers correlated significantly. Furthermore, in the group of all cardiac patients, GPX activity significantly negatively correlated with NT-proBNP (P = 0.050, r = - 0.339) and several markers of inflammation, including TNF-α (P = 0.010, r = - 0.436), interleukin-6 (P = 0.026, r = - 0.382), white blood cell (P = 0.032, r = - 0.369), neutrophil (P = 0.027, r = - 0.379) and monocyte counts (P = 0.024, r = - 0.386). CONCLUSION: Inflammatory and oxidative stress markers are linked in canine CHF patients, but not in patients without CHF. These results suggest complex cross communication between the two biological pathways in advanced stages of CHF.


Assuntos
Doenças do Cão/sangue , Insuficiência Cardíaca/veterinária , Inflamação/veterinária , Estresse Oxidativo , Animais , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Cardiomiopatia Dilatada/sangue , Cardiomiopatia Dilatada/veterinária , Cães , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/metabolismo , Doenças das Valvas Cardíacas/sangue , Doenças das Valvas Cardíacas/veterinária , Contagem de Leucócitos/veterinária , Masculino , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Estudos Prospectivos , Fator de Necrose Tumoral alfa/sangue
20.
Am J Physiol Heart Circ Physiol ; 320(5): H1999-H2010, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33861149

RESUMO

Cardiovascular disease (CVD) is the leading cause of death globally. Current treatment options include lifestyle changes, medication, and surgical intervention. However, many patients are unsuitable candidates for surgeries due to comorbidities, diffuse coronary artery disease, or advanced stages of heart failure. The search for new treatment options has recently transitioned from cell-based therapies to stem-cell-derived extracellular vesicles (EVs). A number of challenges remain in the EV field, including the effect of comorbidities, characterization, and delivery. However, recent revolutionary developments and insight into the potential of personalizing EV contents by bioengineering methods to alter specific signaling pathways in the ischemic myocardium hold promise. Here, we discuss the past limitations of cell-based therapies and recent EV studies involving in vivo, in vitro, and omics, and future challenges and opportunities in EV-based treatments in CVD.


Assuntos
Vesículas Extracelulares/metabolismo , Insuficiência Cardíaca/metabolismo , Células-Tronco Mesenquimais/metabolismo , Isquemia Miocárdica/metabolismo , Animais , Humanos , Miócitos Cardíacos/metabolismo
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