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1.
Antioxidants (Basel) ; 10(10)2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34679760

RESUMO

Reactive oxygen species (ROS) and intracellular iron levels are critical modulators of lipid peroxidation that trigger iron-dependent non-apoptotic ferroptosis in myocardial ischemia-reperfusion (I/R) injury. Histochrome (HC), with a potent antioxidant moiety and iron-chelating capacity, is now available in clinical practice. However, limited data are available about the protective effects of HC on ferroptotic cell death in myocardial I/R injury. In this study, we investigated whether the intravenous administration of HC (1 mg/kg) prior to reperfusion could decrease myocardial damage by reducing ferroptosis. Rats undergoing 60 min of ischemia and reperfusion were randomly divided into three groups as follows: (1) Sham, (2) I/R control, and (3) I/R + HC. Serial echocardiography up to four weeks after I/R injury showed that intravenous injection of HC significantly improved cardiac function compared to the I/R controls. In addition, the hearts of rats who received intravenous injection of HC exhibited significantly lower cardiac fibrosis and higher capillary density. HC treatment decreased intracellular and mitochondrial ROS levels by upregulating the expression of nuclear factor erythroid 2-related factor (Nrf2) and its downstream genes. HC also inhibited erastin- and RSL3-induced ferroptosis in rat neonatal cardiomyocytes by maintaining the intracellular glutathione level and through upregulated activity of glutathione peroxidase 4. These findings suggest that early intervention with HC before reperfusion rescued myocardium from I/R injury by preventing ferroptotic cell death. Therefore, HC is a promising therapeutic option to provide secondary cardioprotection in patients who undergo coronary reperfusion therapy.

2.
Exp Mol Med ; 53(9): 1423-1436, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34584195

RESUMO

Stem cell-based therapies with clinical applications require millions of cells. Therefore, repeated subculture is essential for cellular expansion, which is often complicated by replicative senescence. Cellular senescence contributes to reduced stem cell regenerative potential as it inhibits stem cell proliferation and differentiation as well as the activation of the senescence-associated secretory phenotype (SASP). In this study, we employed MHY-1685, a novel mammalian target of rapamycin (mTOR) inhibitor, and examined its long-term priming effect on the activities of senile human cardiac stem cells (hCSCs) and the functional benefits of primed hCSCs after transplantation. In vitro experiments showed that the MHY-1685‒primed hCSCs exhibited higher viability in response to oxidative stress and an enhanced proliferation potential compared to that of the unprimed senile hCSCs. Interestingly, priming MHY-1685 enhanced the expression of stemness-related markers in senile hCSCs and provided the differentiation potential of hCSCs into vascular lineages. In vivo experiment with echocardiography showed that transplantation of MHY-1685‒primed hCSCs improved cardiac function than that of the unprimed senile hCSCs at 4 weeks post-MI. In addition, hearts transplanted with MHY-1685-primed hCSCs exhibited significantly lower cardiac fibrosis and higher capillary density than that of the unprimed senile hCSCs. In confocal fluorescence imaging, MHY-1685‒primed hCSCs survived for longer durations than that of the unprimed senile hCSCs and had a higher potential to differentiate into endothelial cells (ECs) within the infarcted hearts. These findings suggest that MHY-1685 can rejuvenate senile hCSCs by modulating autophagy and that as a senescence inhibitor, MHY-1685 can provide opportunities to improve hCSC-based myocardial regeneration.

3.
Nat Biomed Eng ; 5(8): 880-896, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34426676

RESUMO

Fibroblasts can be directly reprogrammed into cardiomyocytes, endothelial cells or smooth muscle cells. Here we report the reprogramming of mouse tail-tip fibroblasts simultaneously into cells resembling these three cell types using the microRNA mimic miR-208b-3p, ascorbic acid and bone morphogenetic protein 4, as well as the formation of tissue-like structures formed by the directly reprogrammed cells. Implantation of the formed cardiovascular tissue into the infarcted hearts of mice led to the migration of reprogrammed cells to the injured tissue, reducing regional cardiac strain and improving cardiac function. The migrated endothelial cells and smooth muscle cells contributed to vessel formation, and the migrated cardiomyocytes, which initially displayed immature characteristics, became mature over time and formed gap junctions with host cardiomyocytes. Direct reprogramming of somatic cells to make cardiac tissue may aid the development of applications in cell therapy, disease modelling and drug discovery for cardiovascular diseases.


Assuntos
Células Endoteliais/transplante , Coração/fisiologia , Infarto do Miocárdio/terapia , Miócitos de Músculo Liso/transplante , Regeneração , Animais , Ácido Ascórbico/farmacologia , Proteína Morfogenética Óssea 4/farmacologia , Reprogramação Celular/efeitos dos fármacos , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Junções Comunicantes/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Miocárdio/citologia , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Neovascularização Fisiológica , Transcriptoma
4.
Acta Biomater ; 2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34454081

RESUMO

Myocardial ischemia-reperfusion (IR) generates stress-induced senescent cells (SISCs) that play an important role in the pathophysiology of adverse cardiac remodeling and heart failure via secretion of pro-inflammatory molecules and matrix-degrading proteases. Thus, removal of senescent cells using a senolytic drug could be a potentially effective treatment. However, clinical studies on cancer treatment with a senolytic drug have revealed that systemic administration of a senolytic drug often causes systemic toxicity. Herein we show for the first time that local delivery of a senolytic drug can effectively treat myocardial IR injury. We found that biodegradable poly(lactic-co-glycolic acid) nanoparticle-based local delivery of a senolytic drug (ABT263-PLGA) successfully eliminated SISCs in the IR-injured rat hearts without systemic toxicity. Consequently, the treatment ameliorated inflammatory responses and attenuated adverse remodeling. Surprisingly, the ABT263-PLGA treatment restored the cardiac function over time, whereas the cardiac function decreased over time in the no treatment group. Mechanistically, the ABT263-PLGA treatment not only markedly reduced the expression of pro-inflammatory molecules and matrix-degrading proteases, but also induced macrophage polarization from the inflammatory phase to the reparative phase via efferocytosis of apoptotic SISCs by macrophages. Therefore, the senolytic strategy with ABT263-PLGA in the early stage of myocardial IR injury may be an effective therapeutic option for myocardial infarction. STATEMENT OF SIGNIFICANCE: This study describes a local injection of senolytic drug-loaded nanoparticles that selectively kills stress-induced senescent cells (SISCs) in infarcted heart. Removal of SISCs decreases inflammatory cytokines and normal cell death. We firstly revealed that further efferocytosis of apoptotic senescent cells by macrophages restores cardiac function after myocardial ischemia-reperfusion injury. Importantly, a local injection of senolytic drug did not exhibit systemic toxicity, but a systemic injection did. Our findings not only spotlight the basic understanding of therapeutic potential of senolysis in infarcted myocardium, but also pave the way for the further application of senolytic drug for non-aging related diseases.

5.
Medicine (Baltimore) ; 100(19): e25765, 2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34106607

RESUMO

ABSTRACT: This study evaluated the 5-year clinical outcomes of the Genoss DES, the first Korean-made sirolimus-eluting coronary stent with abluminal biodegradable polymer.We previously conducted the first-in-patient prospective, multicenter, randomized trial with a 1:1 ratio of patients using the Genoss DES and Promus Element stents; the angiographic and clinical outcomes of the Genoss DES stent were comparable to those of the Promus Element stent. The primary endpoint was major adverse cardiac events (MACE), which was a composite of death, myocardial infarction (MI), and target lesion revascularization (TLR) at 5 years.We enrolled 38 patients in the Genoss DES group and 39 in the Promus Element group. Thirty-eight patients (100%) from the Genoss DES group and 38 (97.4%) from the Promus Element group were followed up at 5 years. The rates of MACE (5.3% vs 12.8%, P = .431), death (5.3% vs 10.3%, P = .675), TLR (2.6% vs 2.6%, P = 1.000), and target vessel revascularization (TVR) (7.9% vs 2.6%, P = .358) at 5 years did not differ significantly between the groups. No TLR or target vessel revascularization was reported from years 1 to 5 after the index procedure, and no MI or stent thrombosis occurred in either group during 5 years.The biodegradable polymer Genoss DES and durable polymer Promus Element stents showed comparable low rates of MACE at the 5-year clinical follow-up.


Assuntos
Fármacos Cardiovasculares/administração & dosagem , Doença da Artéria Coronariana/terapia , Stents Farmacológicos , Intervenção Coronária Percutânea/instrumentação , Sirolimo/administração & dosagem , Implantes Absorvíveis , Adulto , Idoso , Idoso de 80 Anos ou mais , Fármacos Cardiovasculares/uso terapêutico , Doença da Artéria Coronariana/mortalidade , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Polímeros , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/prevenção & controle , Estudos Prospectivos , República da Coreia , Sirolimo/uso terapêutico , Resultado do Tratamento
6.
Int J Mol Sci ; 22(3)2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33535594

RESUMO

Human bone marrow-derived mesenchymal stem cells (BM-MSCs), represented as a population of adult stem cells, have long been considered as one of the most promising sources for cell-based cardiac regenerative therapy. However, their clinical use has been significantly hampered by low survival and poor retention following administration into failing hearts. Here, to improve the therapeutic effectiveness of BM-MSCs, we examined a novel therapeutic platform named in situ preconditioning in a rat myocardial infarction (MI) model. In situ preconditioning was induced by a combinatory treatment of BM-MSCs with genetically engineered hepatocyte growth factor-expressing MSCs (HGF-eMSCs) and heart-derived extracellular matrix (hdECM) hydrogel. Subsequently, our results demonstrated that in situ preconditioning with cell mixture substantially improved the survival/retention of BM-MSCs in the MI-induced rat hearts. Enhanced retention of BM-MSCs ultimately led to a significant cardiac function improvement, which was derived from the protection of myocardium and enhancement of vessel formation in the MI hearts. The results provide compelling evidence that in situ preconditioning devised to improve the therapeutic potential of BM-MSCs can be an effective strategy to achieve cardiac repair of MI hearts.


Assuntos
Células da Medula Óssea/citologia , Células-Tronco Mesenquimais/citologia , Infarto do Miocárdio/terapia , Adulto , Animais , Procedimentos Cirúrgicos Cardíacos , Terapia Baseada em Transplante de Células e Tecidos/métodos , Vasos Coronários , Ecocardiografia , Matriz Extracelular/metabolismo , Fibrose , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Masculino , Transplante de Células-Tronco Mesenquimais/métodos , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Isquemia Miocárdica/metabolismo , Miocárdio/metabolismo , Neovascularização Patológica , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Ratos , Regeneração , Células-Tronco/metabolismo , Engenharia Tecidual , Resultado do Tratamento , Adulto Jovem
7.
Korean Circ J ; 51(2): 97-113, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33525065

RESUMO

Mesenchymal stem cells (MSCs) represent a population of adult stem cells residing in many tissues, mainly bone marrow, adipose tissue, and umbilical cord. Due to the safety and availability of standard procedures and protocols for isolation, culturing, and characterization of these cells, MSCs have emerged as one of the most promising sources for cell-based cardiac regenerative therapy. Once transplanted into a damaged heart, MSCs release paracrine factors that nurture the injured area, prevent further adverse cardiac remodeling, and mediate tissue repair along with vasculature. Numerous preclinical studies applying MSCs have provided significant benefits following myocardial infarction. Despite promising results from preclinical studies using animal models, MSCs are not up to the mark for human clinical trials. As a result, various approaches have been considered to promote the therapeutic potency of MSCs, such as genetic engineering, physical treatments, growth factor, and pharmacological agents. Each strategy has targeted one or multi-potentials of MSCs. In this review, we will describe diverse approaches that have been developed to promote the therapeutic potential of MSCs for cardiac regenerative therapy. Particularly, we will discuss major characteristics of individual strategy to enhance therapeutic efficacy of MSCs including scientific principles, advantages, limitations, and improving factors. This article also will briefly introduce recent novel approaches that MSCs enhanced therapeutic potentials of other cells for cardiac repair.

8.
Int J Mol Sci ; 22(3)2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33572816

RESUMO

BCL-2 interacting cell death suppressor (BIS) is a multifunctional protein that has been implicated in cancer and myopathy. Various mutations of the BIS gene have been identified as causative of cardiac dysfunction in some dilated cardiomyopathy (DCM) patients. This was recently verified in cardiac-specific knock-out (KO) mice. In this study, we developed tamoxifen-inducible cardiomyocyte-specific BIS-KO (Bis-iCKO) mice to assess the role of BIS in the adult heart using the Cre-loxP strategy. The disruption of the Bis gene led to impaired ventricular function and subsequent heart failure due to DCM, characterized by reduced left ventricular contractility and dilatation that were observed using serial echocardiography and histology. The development of DCM was confirmed by alterations in Z-disk integrity and increased expression of several mRNAs associated with heart failure and remodeling. Furthermore, aggregation of desmin was correlated with loss of small heat shock protein in the Bis-iCKO mice, indicating that BIS plays an essential role in the quality control of cardiac proteins, as has been suggested in constitutive cardiac-specific KO mice. Our cardiac-specific BIS-KO mice may be a useful model for developing therapeutic interventions for DCM, especially late-onset DCM, based on the distinct phenotypes and rapid progressions.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Cardiomiopatia Dilatada/genética , Animais , Cardiomiopatia Dilatada/patologia , Modelos Animais de Doenças , Feminino , Deleção de Genes , Técnicas de Inativação de Genes , Masculino , Camundongos , Camundongos Knockout , Miocárdio/patologia
9.
Sci Rep ; 11(1): 1783, 2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33469103

RESUMO

Although both angiotensin receptor blockers (ARBs) and dihydropyridine calcium channel blockers (CCBs) are all suitable for the initiation of antihypertensive treatment, studies investigating efficacy and safety between ARBs and CCBs are limited, and there is no previous study comparing their clinical outcomes during long-term follow-up periods in real world setting. We compared cardiovascular (CV) events between ARBs and CCBs in 464,948 hypertensive adults using the Korean National Health Insurance Service database during a 3-year follow-up. The patients with hypertension without heart failure, ischemic heart disease, cerebrovascular disease, or peripheral artery disease were enrolled. The CV events between only single prescription of CCBs and ARBs were finally compared. The primary endpoint for this study was the first occurrence of a major adverse CV events, defined as the composite of all-cause death, cardiac death, nonfatal myocardial infarction, or nonfatal stroke. ARB was significantly more administered in male and patients with higher income, diabetes mellitus, chronic kidney diseases, and higher Charlson comorbidity index. The primary endpoints occurred in 10,526 patients (5.2%) in the ARB group and in 19,363 patients (7.3%) in the CCB group (p < 0.001) during a 3-year follow-up (HR 0.96, 95% CI 0.93-0.98). All the components of CV events including all-cause death, cardiac death, nonfatal myocardial infarction, and nonfatal stroke occurred more frequently in the CCB group. With multivariable models adjusting age, sex, income, diabetes, chronic kidney disease, and Charlson comorbidity index, the primary endpoints less frequently developed in the ARB group than in the CCB group (HR 0.957, 95% CI 0.933-0.983, p < 0.001). After the propensity-score matching, baseline characteristics were similar and still showed significantly better primary endpoints in ARB group than CCB group (5.3% vs. 5.8%, p < 0.001). In this nationwide population-based simple hypertension study, administration of ARBs showed superior protection against CV events than CCBs during a 3-year follow-up. Our results suggest that ARBs could be preferred over CCBs as the initial choice of antihypertensive treatment regardless of age in real-world practice.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Hipertensão/tratamento farmacológico , Adulto , Idoso , Doenças Cardiovasculares/complicações , Feminino , Seguimentos , Humanos , Hipertensão/complicações , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
10.
Antiviral Res ; 184: 104955, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33091434

RESUMO

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is considered as the most significant global public health crisis of the century. Several drug candidates have been suggested as potential therapeutic options for COVID-19, including remdesivir, currently the only authorized drug for use under an Emergency Use Authorization. However, there is only limited information regarding the safety profiles of the proposed drugs, in particular drug-induced cardiotoxicity. Here, we evaluated the antiviral activity and cardiotoxicity of remdesivir using cardiomyocytes-derived from human pluripotent stem cells (hPSC-CMs) as an alternative source of human primary cardiomyocytes (CMs). In this study, remdesivir exhibited up to 60-fold higher antiviral activity in hPSC-CMs compared to Vero E6 cells; however, it also induced moderate cardiotoxicity in these cells. To gain further insight into the drug-induced arrhythmogenic risk, we assessed QT interval prolongation and automaticity of remdesivir-treated hPSC-CMs using a multielectrode array (MEA). As a result, the data indicated a potential risk of QT prolongation when remdesivir is used at concentrations higher than the estimated peak plasma concentration. Therefore, we conclude that close monitoring of the electrocardiographic/QT interval should be advised in SARS-CoV-2-infected patients under remdesivir medication, in particular individuals with pre-existing heart conditions.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/farmacologia , COVID-19/virologia , Miócitos Cardíacos/virologia , Células-Tronco Pluripotentes/citologia , SARS-CoV-2/efeitos dos fármacos , Monofosfato de Adenosina/farmacologia , Alanina/farmacologia , Amidas/farmacologia , Animais , Antimaláricos/farmacologia , COVID-19/complicações , COVID-19/tratamento farmacológico , Chlorocebus aethiops , Cloroquina/farmacologia , Eletrocardiografia , Citometria de Fluxo , Cardiopatias/complicações , Humanos , Hidroxicloroquina/farmacologia , Microscopia de Fluorescência , Miócitos Cardíacos/efeitos dos fármacos , Células-Tronco Pluripotentes/virologia , Pirazinas/farmacologia , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Vero , Ensaio de Placa Viral
11.
Biomater Sci ; 8(16): 4508-4520, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32627794

RESUMO

We previously demonstrated that the efficiency of direct cardiac reprogramming from fibroblasts could be enhanced via mimicking of the in vivo cardiac microenvironment through coculture with cardiomyocytes and by providing electric cues. In the present study, we developed cell sheets using the direct cardiac reprogrammed cells and a nanothin, nanoporous poly(lactic-co-glycolic acid) membrane. Cell sheets were laid layer-by-layer and prevacularized with endothelial cells between the layers. These prevascularized, multilayered cell sheets were implanted on the epicardium of infarcted rat hearts, which led to an improvement in cardiac function and reduction in adverse cardiac remodeling post-myocardial infarction (MI). Thus, the in vivo mimicking direct cardiac reprogramming and prevascularization technique can enhance the efficiency of cell sheets in clinical applications and provide new opportunities to prevent heart failure following MI.


Assuntos
Células Endoteliais , Infarto do Miocárdio , Animais , Técnicas de Cocultura , Fibroblastos , Infarto do Miocárdio/terapia , Miócitos Cardíacos , Ratos
12.
Sci Adv ; 6(18): eaaz0952, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32494669

RESUMO

Because of poor engraftment and safety concerns regarding mesenchymal stem cell (MSC) therapy, MSC-derived exosomes have emerged as an alternative cell-free therapy for myocardial infarction (MI). However, the diffusion of exosomes out of the infarcted heart following injection and the low productivity limit the potential of clinical applications. Here, we developed exosome-mimetic extracellular nanovesicles (NVs) derived from iron oxide nanoparticles (IONPs)-incorporated MSCs (IONP-MSCs). The retention of injected IONP-MSC-derived NVs (IONP-NVs) within the infarcted heart was markedly augmented by magnetic guidance. Furthermore, IONPs significantly increased the levels of therapeutic molecules in IONP-MSCs and IONP-NVs, which can reduce the concern of low exosome productivity. The injection of IONP-NVs into the infarcted heart and magnetic guidance induced an early shift from the inflammation phase to the reparative phase, reduced apoptosis and fibrosis, and enhanced angiogenesis and cardiac function recovery. This approach can enhance the therapeutic potency of an MSC-derived NV therapy.

13.
Sci Adv ; 6(13): eaay6994, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32284967

RESUMO

The clinical use of human bone marrow-derived mesenchymal stem cells (BM-MSCs) has been hampered by their poor performance after transplantation into failing hearts. Here, to improve the therapeutic potential of BM-MSCs, we developed a strategy termed in vivo priming in which BM-MSCs are primed in vivo in myocardial infarction (MI)-induced hearts through genetically engineered hepatocyte growth factor-expressing MSCs (HGF-eMSCs) that are encapsulated within an epicardially implanted 3D cardiac patch. Primed BM-MSCs through HGF-eMSCs exhibited improved vasculogenic potential and cell viability, which ultimately enhanced vascular regeneration and restored cardiac function to the MI hearts. Histological analyses further demonstrated that the primed BM-MSCs survived longer within a cardiac patch and conferred cardioprotection evidenced by substantially higher numbers of viable cardiomyocytes in the MI hearts. These results provide compelling evidence that this in vivo priming strategy can be an effective means to enhance the cardiac repair of MI hearts.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Cardiopatias/terapia , Fator de Crescimento de Hepatócito/genética , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Animais , Técnicas de Cultura de Células , Terapia Baseada em Transplante de Células e Tecidos/métodos , Modelos Animais de Doenças , Expressão Gênica , Engenharia Genética , Cardiopatias/etiologia , Fator de Crescimento de Hepatócito/metabolismo , Fator de Crescimento de Hepatócito/farmacologia , Humanos , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/efeitos dos fármacos , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/terapia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Suínos
14.
Medicine (Baltimore) ; 99(17): e19865, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32332649

RESUMO

The aim of this study was to evaluate the relationship between educational attainment and cardiorespiratory fitness (CRF) as a predictor of metabolic syndrome in a Korean population.In this single-center, retrospective cross-sectional study, 988 healthy adults (601 men and 387 women) who underwent regular health check-up in Seoul St. Mary's Hospital were analyzed. Educational attainment was categorized into 3 groups according to their final grade of educational course: middle or high school (≤12 years of education), college or university (12-16 years of education), and postgraduate (≥16 years of education). CRF was assessed by cardiopulmonary exercise testing, biceps strength, hand grip strength, bioelectrical impedance analysis, and echocardiography. Metabolic syndrome was diagnosed according to the 3rd report of the National Cholesterol Education Program.Among the subjects, 357 (36.1%) had metabolic syndrome. The postgraduate group had significantly higher peak oxygen consumption (VO2), biceps strength, hand grip strength, and peak expiratory flow than other groups (all P < .001). This group showed better left ventricular diastolic function, in terms of deceleration time of mitral inflow, maximal tricuspid valve regurgitation velocity, and left atrial volume index than other groups. Peak VO2 (%) was significantly correlated with all the parameters of metabolic syndrome, including insulin resistance (r = -0.106, P = .002), waist circumference (r = -0.387, P < .001), triglyceride (r = -0.109, P = .001), high density lipoprotein-cholesterol (r = 0.219, P < .001), systolic blood pressure (r = -0.143, P < .001), and diastolic blood pressure (r = -0.177, P < .001). And Peak VO2 (%) was found to be a predictor of metabolic syndrome (adjusted ß = .988, P < .001). However, the level of education was not able to predict metabolic syndrome (postgraduate group; ß = .955, P = .801).Although the postgraduate group had better CRF than other groups, the educational attainment could not exclusively predict metabolic syndrome in this study. Further research is needed to reveal the socioeconomic mechanism of developing metabolic syndrome.


Assuntos
Aptidão Cardiorrespiratória , Escolaridade , Síndrome Metabólica/epidemiologia , Idoso , Fenômenos Fisiológicos Cardiovasculares , Estudos Transversais , Status Econômico , Teste de Esforço , Feminino , Humanos , Masculino , Síndrome Metabólica/fisiopatologia , Pessoa de Meia-Idade , Consumo de Oxigênio , Pico do Fluxo Expiratório , República da Coreia/epidemiologia , Estudos Retrospectivos
16.
Exp Mol Med ; 51(9): 1, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31484921

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

17.
Nat Commun ; 10(1): 3123, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311935

RESUMO

Since both myocardium and vasculature in the heart are excessively damaged following myocardial infarction (MI), therapeutic strategies for treating MI hearts should concurrently target both so as to achieve true cardiac repair. Here we demonstrate a concomitant method that exploits the advantages of cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) and human mesenchymal stem cell-loaded patch (hMSC-PA) to amplify cardiac repair in a rat MI model. Epicardially implanted hMSC-PA provide a complimentary microenvironment which enhances vascular regeneration through prolonged secretion of paracrine factors, but more importantly it significantly improves the retention and engraftment of intramyocardially injected hiPSC-CMs which ultimately restore the cardiac function. Notably, the majority of injected hiPSC-CMs display adult CMs like morphology suggesting that the secretomic milieu of hMSC-PA constitutes pleiotropic effects in vivo. We provide compelling evidence that this dual approach can be a promising means to enhance cardiac repair on MI hearts.


Assuntos
Coração/fisiologia , Transplante de Células-Tronco Mesenquimais/métodos , Infarto do Miocárdio/terapia , Miócitos Cardíacos/transplante , Regeneração , Animais , Diferenciação Celular , Células Cultivadas , Modelos Animais de Doenças , Humanos , Células-Tronco Pluripotentes Induzidas/fisiologia , Injeções Intralesionais , Masculino , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/patologia , Miocárdio/citologia , Miocárdio/patologia , Miócitos Cardíacos/fisiologia , Ratos , Ratos Endogâmicos F344 , Resultado do Tratamento
18.
Acta Biomater ; 95: 188-200, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30986526

RESUMO

Engineered heart tissue (EHT) has ample potential as a model for in vitro tissue modeling or tissue regeneration. Using 3D cell printing technology, various hydrogels have been utilized as bioinks to fabricate EHT to date. However, its efficacy has remained limited due to poor functional properties of the cultured cardiomyocytes stemming from a lack of proper microenvironmental cues. Specifically, the surrounding matrix plays a key role in modulating cardiomyocyte differentiation and maturation. Recently, the use of heart tissue-derived extracellular matrix (hdECM) bioink has come to be seen as one of the most promising candidates due to its functional and structural similarities to native tissue. Here, we demonstrated a correlation between the synthesis of cardiomyocyte-specific proteins and the surrounding microenvironment irrespective of the similar material chemistry. Primary cardiomyocytes isolated from neonatal rats were encapsulated in different composition and concentration of bioinks (hdECM and collagen). The bioinks were sequentially printed using an extrusion-based 3D bioprinter and cultured either statically or dynamically. Qualitative and quantitative evaluation revealed enhanced maturation of cardiomyocytes in hdECM, unlike the collagen group under similar culture conditions. Specifically, 3D-printed EHT using a low concentration of hdECM promoted early differentiation of cardiomyocytes. Hence, the present study provides experimental insights regarding the establishment of a 3D-printed cardiac tissue model, highlighting that the matrix and the culture microenvironment can be decisive factors for cell-material interactions that affect cardiomyocyte maturation. STATEMENT OF SIGNIFICANCE: The regulation of signal transduction and responses to extracellular matrices (ECMs) is of particular relevance in tissue maturation. In particular, there is a clear need to understand the structural and phenotypical modulation in cardiomyocytes with respect to the surrounding microenvironment. Exploration of the key regulators, such as the compositional and the biophysical properties of bioinks associated directly with cell-cell and cell-matrix interactions would assist with the fabrication of cardiac tissue constructs with enhanced functionality. Hence, we documented the synergistic effects of surrounding matrices and culture conditions on the maturation of cardiomyocytes. Additionally, we highlighted the potential of using 3D bioprinting techniques to fabricate uniformly aligned cardiac constructs for mid- to high-throughput drug testing platforms that have great reproducibility and versatility.


Assuntos
Matriz Extracelular/química , Coração/fisiologia , Tinta , Engenharia Tecidual/métodos , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/metabolismo , Animais , Fenômenos Biomecânicos , Cálcio/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Colágeno/farmacologia , Géis , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Reologia , Suínos
19.
Exp Mol Med ; 51(2): 1-14, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30755583

RESUMO

Vascular regeneration in ischemic hearts has been considered a target for new therapeutic strategies. It has been reported that ETV2 is essential for vascular development, injury-induced neovascularization and direct cell reprogramming of non-endothelial cells into endothelial cells. Thus, the objective of this study was to explore the therapeutic potential of ETV2 in murine models of myocardial infarction in vivo. Direct myocardial delivery of lentiviral ETV2 into rodents undergoing myocardial infarction dramatically upregulated the expression of markers for angiogenesis as well as anti-fibrosis and anti-inflammatory factors in vivo. Consistent with these findings, echocardiography showed significantly improved cardiac function in hearts with induced myocardial infarction upon ETV2 injection compared to that in the control virus-injected group as determined by enhanced ejection fraction and fractional shortening. In addition, ETV2-injected hearts were protected against massive fibrosis with a remarkable increase in capillary density. Interestingly, major fractions of capillaries were stained positive for ETV2. In addition, ECs infected with ETV2 showed enhanced proliferation, suggesting a direct role of ETV2 in vascular regeneration in diseased hearts. Furthermore, culture media from ETV2-overexpressing cardiac fibroblasts promoted endothelial cell migration based on scratch assay. Importantly, intramyocardial injection of the adeno-associated virus form of ETV2 into rat hearts with induced myocardial infarction designed for clinical applicability consistently resulted in significant augmentation of cardiac function. We provide compelling evidence that ETV2 has a robust effect on vascular regeneration and enhanced cardiac repair after myocardial infarction, highlighting a potential therapeutic function of ETV2 as an efficient means to treat failing hearts.


Assuntos
Infarto do Miocárdio/genética , Infarto do Miocárdio/fisiopatologia , Neovascularização Fisiológica/genética , Fatores de Transcrição/genética , Transdução Genética , Animais , Linhagem Celular , Movimento Celular , Proliferação de Células , Dependovirus/genética , Modelos Animais de Doenças , Ecocardiografia , Células Endoteliais/metabolismo , Fibroblastos/metabolismo , Fibrose , Fluordesoxiglucose F18 , Expressão Gênica , Vetores Genéticos/genética , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Tomografia por Emissão de Pósitrons , Ratos , Fatores de Transcrição/metabolismo
20.
J Cardiol ; 73(2): 156-162, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30409701

RESUMO

BACKGROUND: Chronic total occlusion (CTO) is a challenging entity in coronary interventions. With improvements in technology and techniques, success rates for percutaneous coronary intervention (PCI) of CTO continue to improve. However, the clinical benefits of PCI remain unclear. The aim of the study was to determine the effectiveness of successful PCI on clinical outcomes using drug-eluting stents in patients with CTO. METHODS: From 2004 to 2010, we analyzed 898 patients with at least one CTO who underwent successful PCI (n=424, 448 lesions) or only medical treatment (n=474, 519 lesions) from a multicenter registry. The primary outcome was all-cause death. RESULTS: During a median of 2.2 years, incidence rate of all-cause death after successful PCI was lower than that after medical treatment (10.6% and 17.5%, p=0.004). However, the multivariate Cox proportional hazards model showed that successful PCI was not associated with improvement in mortality compared to medical treatment [adjusted hazard ratio (HR) 0.84, 95% confidence interval (CI) 0.57-1.24, p=0.38]. Comparable results were obtained after propensity-score matching. Subgroup analysis of propensity-score matched population demonstrated that patients with age under 65 years benefited from successful PCI (HR 0.25, 95% CI 0.08-0.75, p for interaction=0.005). CONCLUSIONS: In patients considered for CTO intervention, medical treatment appears to be associated with a similar mortality compared to successful PCI. Successful CTO PCI might be associated with survival benefit in younger patients compared to medical treatment.


Assuntos
Oclusão Coronária/mortalidade , Stents Farmacológicos/efeitos adversos , Intervenção Coronária Percutânea/mortalidade , Idoso , Doença Crônica , Oclusão Coronária/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Modelos de Riscos Proporcionais , Sistema de Registros , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
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