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1.
Circ Res ; 124(1): 161-169, 2019 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-30605412

RESUMO

On March 1 and 2, 2018, the National Institutes of Health 2018 Progenitor Cell Translational Consortium, Cardiovascular Bioengineering Symposium, was held at the University of Alabama at Birmingham. Convergence of life sciences and engineering to advance the understanding and treatment of heart failure was the theme of the meeting. Over 150 attendees were present, and >40 scientists presented their latest work on engineering human functional myocardium for disease modeling, drug development, and heart failure research. The scientists, engineers, and physicians in the field of cardiovascular sciences met and discussed the most recent advances in their work and proposed future strategies for overcoming the major roadblocks of cardiovascular bioengineering and therapy. Particular emphasis was given for manipulation and using of stem/progenitor cells, biomaterials, and methods to provide molecular, chemical, and mechanical cues to cells to influence their identity and fate in vitro and in vivo. Collectively, these works are profoundly impacting and progressing toward deciphering the mechanisms and developing novel treatments for left ventricular dysfunction of failing hearts. Here, we present some important perspectives that emerged from this meeting.


Assuntos
Disciplinas das Ciências Biológicas , Engenharia Biomédica , Pesquisa Biomédica , Insuficiência Cardíaca , Comunicação Interdisciplinar , Animais , Comportamento Cooperativo , Difusão de Inovações , Coração/fisiopatologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Humanos , Miocárdio/metabolismo , Miocárdio/patologia , Recuperação de Função Fisiológica , Regeneração
2.
Clin Exp Pharmacol Physiol ; 46(8): 743-751, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31063653

RESUMO

Obg-like ATPase 1 (OLA1) that possesses both GTP and ATP hydrolyzing activities has been shown to be involved in translational regulation of cancer cell growth and survival. Also, GSK3ß signalling has been implicated in cardiac development and disease. However, the role of OLA1 in pathological cardiac hypertrophy is unknown. We sought to understand the mechanism by which OLA1 regulates GSK3ß-ß-Catenin signalling and its functional significance in angiotensin-II (ANG II)-induced cardiac hypertrophic response. OLA1 function and its endogenous interaction with GSK3ß/ß-catenin signalling in cultured human ventricular cardiomyocytes (AC16 cells) and mouse hearts (in vivo) was evaluated with/without ANG II-stimulated hypertrophic response. ANG II administration in mice increases myocardial OLA1 protein expression with a corresponding increase in GSK3ß phosphorylation and decrease in ß-Catenin phosphorylation. Cultured cardiomyocytes treated with ANG II show endogenous interaction between OLA1 and GSK3ß, nuclear accumulation of ß-Catenin and significant increase in cell size and expression of hypertrophic marker genes such as atrial natriuretic factor (ANF; NPPA) and ß-myosin heavy chain (MYH7). Intriguingly, OLA1 inhibition attenuates the above hypertrophic response in cardiomyocytes. Taken together, our data suggest that OLA1 plays a detrimental role in hypertrophic response via GSK3ß/ß-catenin signalling. Translation strategies to target OLA1 might potentially limit the underlying molecular derangements leading to left ventricular dysfunction in patients with maladaptive cardiac hypertrophy.


Assuntos
Adenosina Trifosfatases/antagonistas & inibidores , Angiotensina II/farmacologia , Cardiomegalia/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Proteínas de Ligação ao GTP/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , beta Catenina/metabolismo , Animais , Cardiomegalia/induzido quimicamente , Cardiomegalia/patologia , Linhagem Celular , Inibidores Enzimáticos/uso terapêutico , Ventrículos do Coração/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/patologia , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
3.
J Transl Med ; 16(1): 130, 2018 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-29776421

RESUMO

BACKGROUND: Oxidative stress has been linked to heart failure (HF) in humans. Antioxidant-based treatments are often ineffective. Therefore, we hypothesize that some of the HF patients might have a reductive stress (RS) condition. Investigating RS-related mechanisms will aid in personalized optimization of redox homeostasis for better outcomes among HF patients. METHODS: Blood samples were collected from HF patients (n = 54) and healthy controls (n = 42) and serum was immediately preserved in - 80 °C for redox analysis. Malondialdehyde (MDA; lipid peroxidation) levels by HPLC, reduced glutathione (GSH) and its redox ratio (GSH/GSSG) using enzymatic-recycling assay in the serum of HF patients were measured. Further, the activities of key antioxidant enzymes were analyzed by UV-Vis spectrophotometry. Non-invasive echocardiography was used to relate circulating redox status with cardiac function and remodeling. RESULTS: The circulatory redox state (GSH/MDA ratio) was used to stratify the HF patients into normal redox (NR), hyper-oxidative (HO), and hyper-reductive (HR) groups. While the majority of the HF patients exhibited the HO (42%), 41% of them had a normal redox (NR) state. Surprisingly, a subset of HF patients (17%) belonged to the hyper-reductive group, suggesting a strong implication for RS in the progression of HF. In all the groups of HF patients, SOD, GPx and catalase were significantly increased while GR activity was significantly reduced relative to healthy controls. Furthermore, echocardiography analyses revealed that 55% of HO patients had higher systolic dysfunction while 62.5% of the hyper-reductive patients had higher diastolic dysfunction. CONCLUSION: These results suggest that RS may be associated with HF pathogenesis for a subset of cardiac patients. Thus, stratification of HF patients based on their circulating redox status may serve as a useful prognostic tool to guide clinicians designing personalized antioxidant therapies.


Assuntos
Insuficiência Cardíaca/metabolismo , Adulto , Idoso , Antioxidantes , Estudos de Casos e Controles , Diástole , Eletrocardiografia , Feminino , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/enzimologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Oxirredução , Sístole , Remodelação Ventricular
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