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1.
Cell Prolif ; 53(12): e12942, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33107673

RESUMO

INTRODUCTION: Enormous progress has been made in cardiac regeneration using human embryonic stem cell-derived cardiomyocyte (hESC-CM) grafts in pre-clinical trials. However, the rate of cell survival has remained very low due to anoikis after transplantation into the heart as single cells. Numerous solutions have been proposed to improve cell survival, and one of these strategies is to co-transplant biocompatible materials or hydrogels with the hESC-CMs. METHODS: In our study, we screened various combinations of biomaterials that could promote anoikis resistance and improve hESC-CM survival upon co-transplantation and promote cardiac functional recovery. We injected different combinations of Matrigel, alginate and hyaluronate with hESC-CM suspensions into the myocardium of rat models with myocardial infarction (MI). RESULTS: Our results showed that the group treated with a combination of hyaluronate and hESC-CMs had the lowest arrhythmia rates when stimulated with programmed electrical stimulation. While all three combinations of hydrogel-hESC-CM treatments improved rat cardiac function compared with the saline control group, the combination with hyaluronate most significantly reduced pathological changes from left ventricular remodelling and improved both left ventricular function and left ventricular ejection fraction by 28 days post-infarction. CONCLUSION: Hence, we concluded that hyaluronate-hESC-CM is a superior combination therapy for promoting cardiac regeneration after myocardial infarction.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Células-Tronco Embrionárias Humanas/citologia , Ácido Hialurônico/farmacologia , Infarto do Miocárdio/terapia , Miócitos Cardíacos/citologia , Regeneração/fisiologia , Animais , Diferenciação Celular/fisiologia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias Humanas/efeitos dos fármacos , Humanos , Ratos Sprague-Dawley , Função Ventricular Esquerda/fisiologia , Remodelação Ventricular/fisiologia
2.
Am J Physiol Regul Integr Comp Physiol ; 319(4): R476-R484, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32877243

RESUMO

Changes in cardiomyocyte metabolism have been heavily implicated in cardiac injury and heart failure (HF). However, there is emerging evidence that metabolism in nonmyocyte populations, including cardiac fibroblasts, immune cells, and endothelial cells, plays an important role in cardiac remodeling and adaptation to injury. Here, we discuss recent advances and insights into nonmyocyte metabolism in the healthy and injured heart. Metabolic switching from mitochondrial oxidative phosphorylation to glycolysis is critical for immune cell (macrophage and T lymphocyte) and fibroblast phenotypic switching in the inflamed and fibrotic heart. On the other hand, cardiac endothelial cells are heavily reliant on glycolytic metabolism, and thus impairments in glycolytic metabolism underlie endothelial cell dysfunction. Finally, we review current and ongoing metabolic therapies for HF and the potential implications for nonmyocyte metabolism.


Assuntos
Remodelamento Atrial/fisiologia , Fibroblastos/metabolismo , Insuficiência Cardíaca/metabolismo , Miocárdio/metabolismo , Remodelação Ventricular/fisiologia , Células Endoteliais/metabolismo , Glicólise/fisiologia , Humanos , Fosforilação Oxidativa
3.
Int Heart J ; 61(5): 961-969, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32921672

RESUMO

Left ventricular (LV) remodeling with aortic stenosis (AS) appears to differ according to sex, but reverse remodeling after transcatheter aortic valve implantation (TAVI) has not been elucidated in a Japanese population. This study aims to determine whether any sex-related differences in LV or reverse remodeling after TAVI exist in the context of severe AS.Of 208 patients who received TAVI for severe AS in our institution, 100 (men, 42; mean age, 83.0 ± 4.9 years) underwent transthoracic echocardiography before and 3 months after TAVI. Despite similar valvular gradients, women with severe AS had lower indexed LV mass (LVMi) than did men (152.3 ± 35.4 versus 173.2 ± 44.6 g/m2, P = 0.005), with smaller indexed LV end-diastolic (LVEDVi) (50.2 ± 13.3 versus 61.4 ± 20.7 mL/m2, P = 0.001) and end-systolic (LVESVi; 17.9 ± 8.7 versus 24.3 ± 13.8 mL/m2, P = 0.006) volumes. After TAVI, women (-6.0% ± 14.4%) had higher reduction in the rate of change of relative wall thickness (RWT) than did men (4.4% ± 19.0%, P = 0.003). Men (-8.9% ± 3.9%) had higher reduction in the rate of change of LVEDVi than did women (1.5% ± 3.3%, P = 0.045). Incidence of LV reverse remodeling defined as a reduction in LVESV of >15% was significantly higher in men (50%) than in women (26%, P = 0.013).In addition to sex differences in the pattern of LV remodeling with AS, reverse LV remodeling after TAVI also differed between sexes.


Assuntos
Estenose da Valva Aórtica/cirurgia , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Remodelação Ventricular/fisiologia , Idoso , Idoso de 80 Anos ou mais , Estenose da Valva Aórtica/complicações , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/fisiopatologia , Ecocardiografia , Feminino , Humanos , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Japão , Masculino , Índice de Gravidade de Doença , Fatores Sexuais , Substituição da Valva Aórtica Transcateter , Resultado do Tratamento
4.
Am Heart J ; 229: 138-143, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32827459

RESUMO

The present study included 14,550 postmenopausal female participants in the UK Biobank who completed cardiac magnetic resonance imaging. Earlier age at menopause was significantly and independently associated with smaller left ventricular end-diastolic volume and smaller stroke volume, a pattern suggesting acceleration of previously described age-related left ventricular remodeling. These findings may have implications for understanding mechanisms of heart failure, specifically heart failure with preserved ejection fraction, among women with early menopause.


Assuntos
Ventrículos do Coração , Menopausa Precoce/fisiologia , Menopausa/fisiologia , Volume Sistólico/fisiologia , Remodelação Ventricular/fisiologia , Feminino , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Imagem Cinética por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Tamanho do Órgão
5.
Life Sci ; 259: 118199, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32781064

RESUMO

Cellular senescence, a process whereby cells enter a state of permanent growth arrest, appears to regulate cardiac pathological remodeling and dysfunction in response to various stresses including myocardial infarction (MI). However, the precise role as well as the underlying regulatory mechanism of cardiac cellular senescence in the ischemic heart disease remain to be further determined. Herein we report an inhibitory role of Nrf2, a key transcription factor of cellular defense, in regulating cardiac senescence in infarcted hearts as well as a therapeutic potential of targeting Nrf2-mediated suppression of cardiac senescence in the treatment of MI-induced cardiac dysfunction. MI was induced by left coronary artery ligation for 28 days in mice. Heart tissues from the infarct border zone were used for the analyses. The MI-induced cardiac dysfunction was associated with increased myocardial cell senescence, oxidative stress and apoptosis in adult wild type (WT) mice. In addition, a downregulated Nrf2 activity was associated with upregulated Keap1 levels and increased phosphorylation of JAK and FYN in the infarcted border zone heart tissues. Nrf2 Knockout (Nrf2-/-) enhanced the MI-induced myocardial, cardiac dysfunction and senescence. Qiliqiangxin (QLQX), a herbal medicine which could reverse the MI-induced suppression of Nrf2 activity, significantly inhibited the MI-induced cardiac senescence, apoptosis, and cardiac dysfunction in WT mice but not in Nrf2-/- mice. These results indicate that MI downregulates Nrf2 activity thus promoting oxidative stress to accelerate cellular senescence in the infarcted heart towards cardiac dysfunction and Nrf2 may be a drug target for suppressing the cellular senescence-associated pathologies in infarcted hearts.


Assuntos
Cardiomiopatias/genética , Cardiomiopatias/patologia , Senescência Celular/genética , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Miocárdio/patologia , Fator 2 Relacionado a NF-E2/genética , Animais , Cardiomiopatias/diagnóstico por imagem , Ecocardiografia , Inativação Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infarto do Miocárdio/diagnóstico por imagem , Miócitos Cardíacos/metabolismo , RNA Interferente Pequeno/farmacologia , Remodelação Ventricular/fisiologia
6.
Sci Rep ; 10(1): 13926, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32811872

RESUMO

Cardiac tissue remodeling caused by hemodynamic overload is a major clinical outcome of heart failure. Uridine-responsive purinergic P2Y6 receptor (P2Y6R) contributes to the progression of cardiovascular remodeling in rodents, but it is not known whether inhibition of P2Y6R prevents or promotes heart failure. We demonstrate that inhibition of P2Y6R promotes pressure overload-induced sudden death and heart failure in mice. In neonatal cardiomyocytes, knockdown of P2Y6R significantly attenuated hypertrophic growth and cell death caused by hypotonic stimulation, indicating the involvement of P2Y6R in mechanical stress-induced myocardial dysfunction. Unexpectedly, compared with wild-type mice, deletion of P2Y6R promoted pressure overload-induced sudden death, as well as cardiac remodeling and dysfunction. Mice with cardiomyocyte-specific overexpression of P2Y6R also exhibited cardiac dysfunction and severe fibrosis. In contrast, P2Y6R deletion had little impact on oxidative stress-mediated cardiac dysfunction induced by doxorubicin treatment. These findings provide overwhelming evidence that systemic inhibition of P2Y6R exacerbates pressure overload-induced heart failure in mice, although P2Y6R in cardiomyocytes contributes to the progression of cardiac fibrosis.


Assuntos
Insuficiência Cardíaca/fisiopatologia , Receptores Purinérgicos P2/metabolismo , Remodelação Ventricular/genética , Animais , Doxorrubicina/farmacologia , Fibrose/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2/genética , Transdução de Sinais/genética , Estresse Mecânico , Remodelação Ventricular/fisiologia
7.
Sci Rep ; 10(1): 14129, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32839504

RESUMO

Cardiac myocytes have multiple cell autonomous mechanisms that facilitate stabilization and repair of damaged sarcolemmal membranes following myocardial injury. Dysferlin is a protein which facilitates membrane repair by promoting membrane resealing. Although prior studies have shown that dysferlin-deficient (Dysf-/-) mouse hearts have an impaired recovery from acute ischemia/reperfusion (I/R) injury ex vivo, the role of dysferlin in mediating the recovery from myocardial injury in vivo is unknown. Here we show that Dysf-/- mice develop adverse LV remodeling following I/R injury secondary to the collateral damage from sustained myocardial inflammation within the infarct zone. Backcrossing Dysf-/- mice with mice lacking signaling through the Toll-Interleukin 1 Receptor Domain-Containing Adaptor Protein (Tirap-/-), attenuated inflammation and abrogated adverse LV remodeling following I/R injury. Subsequent studies using Poloxamer 188 (P188), a membrane resealing reagent, demonstrated that P188 did not attenuate inflammation nor prevent adverse LV remodeling in Dysf-/- mice following I/R injury. Viewed together these studies reveal a previously unappreciated role for the importance of membrane sealing and the resolution of inflammation following myocardial injury.


Assuntos
Disferlina/genética , Glicoproteínas de Membrana/metabolismo , Isquemia Miocárdica/patologia , Receptores de Interleucina-1/metabolismo , Traumatismo por Reperfusão/patologia , Remodelação Ventricular/fisiologia , Animais , Cardiotônicos/farmacologia , Disferlina/deficiência , Inflamação/patologia , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/patologia , Fosfolipídeos/metabolismo , Poloxâmero/farmacologia , Receptores de Interleucina-1/genética , Sarcolema/fisiologia , Transdução de Sinais , Tensoativos/farmacologia
8.
Life Sci ; 257: 118047, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32629001

RESUMO

AIM: The purpose of the study was to investigate what effects the sigma-1 receptor (S1R) could exert on the cardiac myocyte ion channels in a rodent model of depression and to explore the underlying mechanisms since depression is an independent risk factor for cardiovascular diseases including ventricular arrhythmias (VAs). MATERIALS AND METHODS: To establish the depression model in rats, chronic mild unpredictable stress (CMUS) for 28 days was used. The S1R agonist fluvoxamine was injected intraperitoneally from the second week to the last week for 21 days in total, and the effects were evaluated by patch clamp, western blot analysis, and Masson staining. KEY FINDINGS: We demonstrated that depression was improved after treatment with fluvoxamine. In addition, the prolongation of the corrected QT (QTc) interval under CMUS that increased vulnerability to VAs was significantly attenuated by stimulation of S1R due to the decreased amplitude of L-type calcium current (ICa-L) and the restoration of reduced transient outward potassium current (Ito) resulting from CMUS induction. The S1R also decelerated Ito inactivation and accelerated Ito recovery by activating Ca2+/calmodulin-dependent kinase II. Moreover, the stimulation of S1R ameliorated the structural remodeling as the substrate for maintenance of VAs. All these effects were abolished by the administration of S1R antagonist BD1047, which verified the roles for S1R. SIGNIFICANCE: Activation of S1R could decrease the vulnerability to VAs by inhibiting ICa-L and restoring Ito, in addition to ameliorating the CMUS-induced depressive symptoms and structural remodeling.


Assuntos
Depressão/metabolismo , Miócitos Cardíacos/metabolismo , Receptores sigma/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Arritmias Cardíacas/metabolismo , Depressão/fisiopatologia , Transtorno Depressivo/metabolismo , Transtorno Depressivo/fisiopatologia , Modelos Animais de Doenças , Fluvoxamina/metabolismo , Fluvoxamina/farmacologia , Ventrículos do Coração/efeitos dos fármacos , Canais Iônicos/efeitos dos fármacos , Canais Iônicos/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Receptores sigma/metabolismo , Remodelação Ventricular/efeitos dos fármacos , Remodelação Ventricular/fisiologia
9.
Clin Interv Aging ; 15: 853-863, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606625

RESUMO

Purpose: There have been few recent studies regarding vascular aging and its relationship with left ventricular (LV) geometry. Moreover, the association of abnormal LV geometry with various kinds of vascular aging has not yet been systematically analyzed. Thus, this study aimed to further elucidate this relationship. Materials and Methods: In this study, 3363 older participants (43.6% male, aged 71.1±5.9 years; 56.4% female, aged 71.1±6.1 years) derived from the Northern Shanghai Study were enrolled. Vascular aging criteria included arteriosclerosis, defined as carotid-femoral pulse wave velocity >10 m/s or brachial-ankle pulse wave velocity >1800 cm/s, and peripheral atherosclerosis, defined as ankle-brachial index <0.9, carotid artery intima-media thickness (cIMT) greater than 0.9 mm, or carotid plaque indicating carotid artery abnormality. Micro-albuminuria was defined as urinary albumin-to-creatinine ratio >30 mg/g. Decreased estimated glomerular filtration rate (eGFR) was defined as eGFR <60 mL/min/1.73 m2. Results: When vascular aging parameters were respectively adjusted for age and sex, arteriosclerosis, micro-albuminuria, and peripheral atherosclerosis were significantly associated with concentric remodeling, eccentric LV hypertrophy (LVH), and concentric LVH (P<0.045) but not with decreased eGFR or abnormal cIMT and presence of plaque. Peripheral atherosclerosis was strongly associated with LV concentric geometry (LVCG) when considering other covariates (risk factors, diseases, and treatments) (P<0.012). Conclusion: Vascular aging parameters such as arteriosclerosis, micro-albuminuria, and peripheral atherosclerosis are significantly and independently associated with LVCG in community-dwelling older Chinese population, suggesting the importance of vascular aging during early clinical assessment of abnormal LV geometry change and serious cardiovascular events.


Assuntos
Espessura Intima-Media Carotídea/normas , Hipertensão/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Placa Aterosclerótica/diagnóstico por imagem , Remodelação Ventricular/fisiologia , Idoso , Índice Tornozelo-Braço , Artérias Carótidas/fisiopatologia , China/epidemiologia , Feminino , Ventrículos do Coração/fisiopatologia , Humanos , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Vida Independente , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Placa Aterosclerótica/fisiopatologia , Estudos Prospectivos , Análise de Onda de Pulso , Fatores de Risco
10.
Am J Respir Cell Mol Biol ; 63(5): 652-664, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32692928

RESUMO

Pulmonary hypertension (PH) and right ventricular (RV) hypertrophy frequently develop in patients with hypoxic lung disease. Chronic alveolar hypoxia (CH) promotes sustained pulmonary vasoconstriction and pulmonary artery (PA) remodeling by acting on lung cells, resulting in the development of PH. RV hypertrophy develops in response to PH, but coronary arterial hypoxemia in CH may influence that response by activating HIF-1α (hypoxia-inducible factor 1α) and/or HIF-2α in cardiomyocytes. Indeed, other studies show that the attenuation of PH in CH fails to prevent RV remodeling, suggesting that PH-independent factors regulate RV hypertrophy. Therefore, we examined the role of HIFs in RV remodeling in CH-induced PH. We deleted HIF-1α and/or HIF-2α in hearts of adult mice that were then housed under normoxia or CH (10% O2) for 4 weeks. RNA-sequencing analysis of the RV revealed that HIF-1α and HIF-2α regulate the transcription of largely distinct gene sets during CH. RV systolic pressure increased, and RV hypertrophy developed in CH. The deletion of HIF-1α in smooth muscle attenuated the CH-induced increases in RV systolic pressure but did not decrease hypertrophy. The deletion of HIF-1α in cardiomyocytes amplified RV remodeling; this was abrogated by the simultaneous loss of HIF-2α. CH decreased stroke volume and cardiac output in wild-type but not in HIF-1α-deficient hearts, suggesting that CH may cause cardiac dysfunction via HIF-dependent signaling. Collectively, these data reveal that HIF-1 and HIF-2 act together in RV cardiomyocytes to orchestrate RV remodeling in CH, with HIF-1 playing a protective role rather than driving hypertrophy.


Assuntos
Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia/complicações , Função Ventricular Direita/fisiologia , Remodelação Ventricular/fisiologia , Animais , Doença Crônica , Deleção de Genes , Regulação da Expressão Gênica , Ontologia Genética , Hipertensão Pulmonar/genética , Integrases/metabolismo , Camundongos , Miócitos Cardíacos/metabolismo , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Transcrição Genética , Função Ventricular Direita/genética , Remodelação Ventricular/genética
11.
BMC Vet Res ; 16(1): 262, 2020 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-32727469

RESUMO

BACKGROUND: Following myocardial infarction (MI), we aimed to characterize morphometric and genetic changes in extracellular matrix (ECM) components from ischemia onset until late phases after coronary reperfusion in necrotic and salvaged myocardium. RESULTS: Swine were divided into one control (n = 5) and three MI groups: 90-min of ischemia without reperfusion, or followed by 1-week or 1-month reperfusion (n = 5 per group). In samples from the necrotic and salvaged areas, ECM components were morphometrically quantified and mRNA levels of factors involved in ECM remodeling were evaluated. After 90-min of ischemia, fibronectin, laminin, and elastic fibers content as well as upregulated mRNA expression of tissue inhibitors of metalloproteinases (TIMP)1, TIMP2, TIMP3 and connective tissue growth factor increased in the necrotic and salvaged myocardium. In both reperfused MI groups, collagen-I, collagen-III, elastic fibers, glycosaminoglycans, laminin, and fibronectin levels heightened in the necrotic but not the salvaged myocardium. Moreover, mRNA expression of TIMP1, TIMP2 and TIMP3, as well as metalloproteinase-2 and metalloproteinase-9 heightened in the necrotic but not in the salvaged myocardium. CONCLUSIONS: Matrix remodeling starts after ischemia onset in both necrotic and salvaged myocardium. Even if ECM composition from the salvaged myocardium was altered after severe ischemia, ECM makes a full recovery to normal composition after reperfusion. Therefore, rapid coronary reperfusion is essential not only to save cardiomyocytes but also to preserve matrix, thus avoiding impaired left ventricular remodeling.


Assuntos
Matriz Extracelular/patologia , Infarto do Miocárdio/fisiopatologia , Reperfusão Miocárdica , Animais , Colágeno/metabolismo , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Matriz Extracelular/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Feminino , Modelos Animais , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sus scrofa , Inibidores Teciduais de Metaloproteinases/metabolismo , Remodelação Ventricular/fisiologia
12.
Am J Pathol ; 190(9): 1789-1800, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32473918

RESUMO

We studied the role of galectin-3 (Gal-3) in the expression of alternative activation markers (M2) on macrophage, cytokines, and fibrosis through the temporal evolution of healing, ventricular remodeling, and function after myocardial infarction (MI). C57BL/6J and Gal-3 knockout mice (Lgals3-/-) were subjected to permanent coronary ligation or sham. We studied i) mortality, ii) macrophage infiltration and expression of markers of alternative activation, iii) cytokine, iv) matrix metalloproteinase-2 activity, v) fibrosis, and vi) cardiac function and remodeling. At 1 week post-MI, lack of Gal-3 markedly attenuated F4/80+ macrophage infiltration and significantly increased the expression of Mrc1 and Chil1, markers of M2 macrophages at the MI zone. Levels of IL-10, IL-6, and matrix metalloproteinase-2 were significantly increased, whereas tumor necrosis factor-α, transforming growth factor-ß, and fibrosis were remarkably attenuated at the infarct zone. In Gal-3 knockout mice, scar thinning ratio, expansion, and cardiac remodeling and function were severely affected from the onset of MI. At 4 weeks post-MI, the natural evolution of fibrosis in Gal-3 knockout mice was also affected. Our results suggest that Gal-3 is essential for wound healing because it regulates the dynamics of macrophage infiltration, proinflammatory and anti-inflammatory cytokine expression, and fibrosis along the temporal evolution of MI in mice. The deficit of Gal-3 affected the dynamics of wound healing, thus aggravating the evolution of remodeling and function.


Assuntos
Galectina 3/metabolismo , Macrófagos/patologia , Infarto do Miocárdio/patologia , Remodelação Ventricular/fisiologia , Cicatrização/fisiologia , Animais , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infarto do Miocárdio/metabolismo
13.
Biochem Pharmacol ; 178: 114065, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32492448

RESUMO

At present, ischemic heart failure (HF) caused by coronary heart disease (CHD) has a high morbidity and mortality, placing a heavy burden on global human health. L-Proline (Pro), a nonessential amino acid and the foundation of proteins in the human body, was found to be protective against oxidative stress in various diseases. However, the role of Pro in cardiovascular disease (CVD) remains unclear. In vivo, adult mice were subjected to left anterior descending (LAD) artery ligation for 4 weeks with or without Pro treatment. In vitro, H9c2 cardiomyocytes were pretreated with or without Pro, followed by treatment with hydrogen peroxide (H2O2) (200 µM) for 6 and 12 h. Our data showed that Pro metabolism was disturbing after myocardial infarction (MI). Pro treatment improved cardiac remodeling, reduced infarct size, and decreased oxidative stress and apoptosis in mouse hearts after MI. Pro inhibited the H2O2-induced increase in reactive oxygen species (ROS) in H9c2 cells and protected against H2O2-induced apoptosis. Mechanistically, by RNA sequencing (RNA-seq) and pathway analysis, Pro was shown to exert a protective effect through H2O2 catabolic processes and apoptotic processes, especially oxidative phosphorylation (OXPHOS). Taken together, our findings suggested that Pro protects against MI injury at least partially via redox regulation, highlighting the potential of Pro as a novel therapy for ischemic HF caused by CHD.


Assuntos
Apoptose/efeitos dos fármacos , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Prolina/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Apoptose/fisiologia , Linhagem Celular , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Miócitos Cardíacos/patologia , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Prolina/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Remodelação Ventricular/fisiologia
14.
J Vis Exp ; (159)2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32510479

RESUMO

Mitral regurgitation (MR) is a widely prevalent heart valve lesion, which causes cardiac remodeling and leads to congestive heart failure. Though the risks of uncorrected MR and its poor prognosis are known, the longitudinal changes in cardiac function, structure and remodeling are incompletely understood. This knowledge gap has limited our understanding of the optimal timing for MR correction, and the benefit that early versus late MR correction may have on the left ventricle. To investigate the molecular mechanisms that underlie left ventricular remodeling in the setting of MR, animal models are necessary. Traditionally, the aorto-caval fistula model has been used to induce volume overload, which differs from clinically relevant lesions such as MR. MR represents a low-pressure volume overload hemodynamic stressor, which requires animal models that mimic this condition. Herein, we describe a rodent model of severe MR in which the anterior leaflet of the rat mitral valve is perforated with a 23G needle, in a beating heart, with echocardiographic image guidance. The severity of MR is assessed and confirmed with echocardiography, and the reproducibility of the model is reported.


Assuntos
Insuficiência da Valva Mitral/diagnóstico por imagem , Remodelação Ventricular/fisiologia , Animais , Modelos Animais de Doenças , Insuficiência da Valva Mitral/fisiopatologia , Ratos , Resultado do Tratamento
15.
Sci Rep ; 10(1): 9459, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32528051

RESUMO

Coronary heart disease is a leading cause of death. Tissue remodeling and fibrosis results in cardiac pump dysfunction and ischemic heart failure. Cardiac fibroblasts may rebuild damaged tissues when prompted by suitable environmental cues. Here, we use acellular biologic extracellular matrix scaffolds (bioscaffolds) to stimulate pathways of muscle repair and restore tissue function. We show that acellular bioscaffolds with bioinductive properties can redirect cardiac fibroblasts to rebuild microvascular networks and avoid tissue fibrosis. Specifically, when human cardiac fibroblasts are combined with bioactive scaffolds, gene expression is upregulated and paracrine mediators are released that promote vasculogenesis and prevent scarring. We assess these properties in rodents with myocardial infarction and observe bioscaffolds to redirect fibroblasts, reduce tissue fibrosis and prevent maladaptive structural remodeling. Our preclinical data confirms that acellular bioscaffold therapy provides an appropriate microenvironment to stimulate pathways of functional repair. We translate our observations to patients with coronary heart disease by conducting a first-in-human observational cohort study. We show that bioscaffold therapy is associated with improved perfusion of infarcted myocardium, reduced myocardial scar burden, and reverse structural remodeling. We establish that clinical use of acellular bioscaffolds is feasible and offers a new frontier to enhance surgical revascularization of ischemic heart muscle.


Assuntos
Fibroblastos/patologia , Traumatismos Cardíacos/patologia , Infarto do Miocárdio/patologia , Miocárdio/patologia , Animais , Linhagem Celular , Cicatriz/patologia , Estudos de Coortes , Matriz Extracelular/patologia , Fibrose/patologia , Coração/fisiopatologia , Humanos , Masculino , Ratos , Roedores , Tecidos Suporte , Remodelação Ventricular/fisiologia
16.
Life Sci ; 254: 117761, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32413403

RESUMO

With the increase of an aging population and the rising incidence of cardiovascular diseases, heart failure (HF) patients are on the rise every year. Myocardial infarction (MI) is the leading cause of HF in patients among cardiovascular diseases. In clinic, patients with MI are often assessed by biochemical indicators, electrocardiography, brain natriuretic peptide levels, myocardial enzymology, echocardiography and other means to predict the occurrence of HF and ventricular remodeling (VR). But there is still a lack of more accurate evaluation. VR is the basic mechanism of HF. In recent years, the molecular mechanism of VR has been studied mainly from the aspects of myocardial hypertrophy, myocardial fibrosis, inflammation, myocardial energy disorder, apoptosis, autophagy and pyroptosis. Exosomes are considered as the main mediators of intercellular information transmission. In addition, exosomes can promote the migration and transformation of intercellular RNAs, which are highly conserved non-coding RNAs. They can mediate the process of cell proliferation and differentiation of the target cell membrane. Exosomes have protective effects on VR after MI by inhibiting fibrosis, promoting angiogenesis and inhibiting inflammation and pyroptosis. We reviewed the specific protective mechanisms of exosomes for VR after MI. In addition, we discussed the formation of targeted exosomes and the role of non-coding RNAs in VR.


Assuntos
Exossomos/fisiologia , RNA não Traduzido/metabolismo , Remodelação Ventricular/fisiologia , Animais , Exossomos/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , RNA não Traduzido/genética , Função Ventricular Esquerda , Remodelação Ventricular/genética
17.
J Vis Exp ; (158)2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32420983

RESUMO

In response to an injury, such as myocardial infarction, prolonged hypertension or a cardiotoxic agent, the heart initially adapts through the activation of signal transduction pathways, to counteract, in the short-term, for the cardiac myocyte loss and or the increase in wall stress. However, prolonged activation of these pathways becomes detrimental leading to the initiation and propagation of cardiac remodeling leading to changes in left ventricular geometry and increases in left ventricular volumes; a phenotype seen in patients with systolic heart failure (HF). Here, we describe the creation of a rat model of pressure overload induced moderate remodeling and early systolic dysfunction (MOD) by ascending aortic banding (AAB) via a vascular clip with an internal area of 2 mm2. The surgery is performed in 200 g Sprague-Dawley rats. The MOD HF phenotype develops at 8-12 weeks after AAB and is characterized noninvasively by means of echocardiography. Previous work suggests the activation of signal transduction pathways and altered gene expression and post-translational modification of proteins in the MOD HF phenotype that mimic those seen in human systolic HF; therefore, making the MOD HF phenotype a suitable model for translational research to identify and test potential therapeutic anti-remodeling targets in HF. The advantages of the MOD HF phenotype compared to the overt systolic HF phenotype is that it allows for the identification of molecular targets involved in the early remodeling process and the early application of therapeutic interventions. The limitation of the MOD HF phenotype is that it may not mimic the spectrum of diseases leading to systolic HF in human. Moreover, it is a challenging phenotype to create, as the AAB surgery is associated with high mortality and failure rates with only 20% of operated rats developing the desired HF phenotype.


Assuntos
Modelos Animais de Doenças , Insuficiência Cardíaca Sistólica/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Volume Sistólico , Remodelação Ventricular/fisiologia , Animais , Pressão Sanguínea , Ecocardiografia , Ratos , Ratos Sprague-Dawley
18.
PLoS One ; 15(5): e0232427, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32369506

RESUMO

Hypertrophic cardiomyopathy (HCM) is the most frequent genetic cardiac disease with a prevalence of 1:500 to 1:200. While most patients show obstructive HCM and a relatively stable clinical phenotype (stage II), a small group of patients progresses to end-stage HCM (stage IV) within a relatively brief period. Previous research has shown sex-differences in stage II HCM with more diastolic dysfunction in female than in male patients. Moreover, female patients more often show progression to heart failure. Here we investigated if differences in functional and structural properties of the heart may underlie sex-differences in disease progression from stage II to stage IV HCM. Cardiac tissue from stage II and IV patients was obtained during myectomy (n = 54) and heart transplantation (n = 10), respectively. Isometric force was measured in membrane-permeabilized cardiomyocytes to define active and passive myofilament force development. Titin isoform composition was assessed using gel electrophoresis, and the amount of fibrosis and capillary density were determined with histology. In accordance with disease stage-dependent adverse cardiac remodeling end-stage patients showed a thinner interventricular septal wall and larger left ventricular and atrial diameters compared to stage II patients. Cardiomyocyte contractile properties and fibrosis were comparable between stage II and IV, while capillary density was significantly lower in stage IV compared to stage II. Women showed more adverse cellular remodeling compared to men at stage II, evident from more compliant titin, more fibrosis and lower capillary density. However, the disease stage-dependent reduction in capillary density was largest in men. In conclusion, the more severe cellular remodeling in female compared to male stage II patients suggests a more advanced disease stage at the time of myectomy in women. Changes in cardiomyocyte contractile properties do not explain the progression of stage II to stage IV, while reduced capillary density may underlie disease progression to end-stage heart failure.


Assuntos
Cardiomiopatia Hipertrófica/patologia , Remodelação Ventricular/fisiologia , Adolescente , Adulto , Idoso , Capilares/patologia , Miosinas Cardíacas/genética , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/fisiopatologia , Proteínas de Transporte/genética , Estudos de Casos e Controles , Criança , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Miócitos Cardíacos/patologia , Miócitos Cardíacos/fisiologia , Cadeias Pesadas de Miosina/genética , Fatores de Risco , Caracteres Sexuais , Troponina T/genética , Remodelação Ventricular/genética , Adulto Jovem
19.
PLoS One ; 15(5): e0232399, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32374790

RESUMO

Heart failure with a preserved ejection fraction (HFpEF) is associated with multiple comorbidities, such as old age, hypertension, type 2 diabetes and obesity and is more prevalent in females. Although the male obese ZSF1 rat has been proposed as a suitable model to study the development of diastolic dysfunction and early HFpEF, studies in female animals have not been performed yet. Therefore, we aimed to characterize the cardiac phenotype in female obese ZSF1 rats and their lean counterparts. Additionally, we aimed to investigate whether differences exist in disease progression in obese male and female ZSF1 rats. Therefore, male and female ZSF1 rats, lean as well as obese (N = 6-9/subgroup), were used. Every two weeks, from 12 to 26 weeks of age, systolic blood pressure and echocardiographic measurements were performed, and venous blood was sampled. Female obese ZSF1 rats, as compared to female lean ZSF1 rats, developed diastolic dysfunction with cardiac hypertrophy and fibrosis in the presence of severe dyslipidemia, increased plasma growth differentiation factor 15 and mild hypertension, and preservation of systolic function. Although obese female ZSF1 rats did not develop hyperglycemia, their diastolic dysfunction was as severe as in the obese males. Taken together, the results from the present study suggest that the female obese ZSF1 rat is a relevant animal model for HFpEF with multiple comorbidities, suitable for investigating novel therapeutic interventions.


Assuntos
Insuficiência Cardíaca/etiologia , Obesidade/complicações , Animais , Pressão Sanguínea/fisiologia , Colágeno/metabolismo , Diástole/fisiologia , Modelos Animais de Doenças , Ecocardiografia , Feminino , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/fisiopatologia , Masculino , Síndrome Metabólica/complicações , Miocárdio/metabolismo , Miocárdio/patologia , Ratos , Ratos Endogâmicos SHR , Ratos Zucker , Caracteres Sexuais , Volume Sistólico/fisiologia , Magreza/fisiopatologia , Remodelação Ventricular/fisiologia
20.
Am J Physiol Heart Circ Physiol ; 318(6): H1525-H1537, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32383996

RESUMO

Growing evidence shows that activation of inflammation in the heart provokes left ventricular (LV) remodeling and dysfunction in humans and experimental animals with heart failure (HF). Moreover, recent studies found that cyclic GMP-AMP synthase (cGAS), serving as a cytosolic DNA sensor, was essential for activating innate immunity against infection and cellular damage by initiating the STING-IRFs-type I IFN signaling cascade, which played important roles in regulating the inflammatory response. However, the pathophysiological role of cGAS in pressure overload-induced HF is unclear. Wild-type C57BL/6J mice and cGAS inhibition mice were subjected to transverse aortic constriction (TAC) to induce HF or sham operation. Inhibition of cGAS in the murine heart was performed using adeno-associated virus 9 (AAV9). Alterations of the cGAS/STING pathway were examined by qPCR and Western blotting. Cardiac remodeling was assessed by echocardiography as well as histological and molecular phenotyping. Compared with sham-operated mice, the cGAS/STING pathway was activated in LV tissues in TAC mice. Whereas TAC mice exhibited significant pathological cardiac remodeling and LV dysfunction, inhibition of cGAS improved early survival rates after TAC, preserved LV contractile function, and blunted pathological remodeling, including cardiac hypertrophy, fibrosis, and apoptosis. Furthermore, downregulation of cGAS diminished early inflammatory cell infiltration and inflammatory cytokine expression in response to TAC. These results demonstrated that cGAS played an essential pathogenetic role in pressure overload-induced HF to promote pathological cardiac remodeling and dysfunction. Our results suggest that inhibition of cGAS may be a novel therapeutic approach for HF.NEW & NOTEWORTHY In this study, we first revealed a novel role of cGAS in the regulation of pathological cardiac remodeling and dysfunction upon pressure overload. We found that the cGAS/STING pathway was activated during pressure overload. Moreover, we also demonstrated that inhibition of the cGAS/STING pathway alleviated pathological cardiac remodeling and downregulated the early inflammatory response during pressure overload-induced HF. Together, these findings will provide a new therapeutic target for HF.


Assuntos
Pressão Sanguínea/fisiologia , Insuficiência Cardíaca/metabolismo , Proteínas de Membrana/metabolismo , Nucleotidiltransferases/metabolismo , Remodelação Ventricular/fisiologia , Animais , Coração/fisiopatologia , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Transgênicos , Nucleotidiltransferases/genética , Transdução de Sinais
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