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1.
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
2.
Int J Mol Sci ; 22(15)2021 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-34360689

RESUMO

Macrophages were first described as phagocytic immune cells responsible for maintaining tissue homeostasis by the removal of pathogens that disturb normal function. Historically, macrophages have been viewed as terminally differentiated monocyte-derived cells that originated through hematopoiesis and infiltrated multiple tissues in the presence of inflammation or during turnover in normal homeostasis. However, improved cell detection and fate-mapping strategies have elucidated the various lineages of tissue-resident macrophages, which can derive from embryonic origins independent of hematopoiesis and monocyte infiltration. The role of resident macrophages in organs such as the skin, liver, and the lungs have been well characterized, revealing functions well beyond a pure phagocytic and immunological role. In the heart, recent research has begun to decipher the functional roles of various tissue-resident macrophage populations through fate mapping and genetic depletion studies. Several of these studies have elucidated the novel and unexpected roles of cardiac-resident macrophages in homeostasis, including maintaining mitochondrial function, facilitating cardiac conduction, coronary development, and lymphangiogenesis, among others. Additionally, following cardiac injury, cardiac-resident macrophages adopt diverse functions such as the clearance of necrotic and apoptotic cells and debris, a reduction in the inflammatory monocyte infiltration, promotion of angiogenesis, amelioration of inflammation, and hypertrophy in the remaining myocardium, overall limiting damage extension. The present review discusses the origin, development, characterization, and function of cardiac macrophages in homeostasis, cardiac regeneration, and after cardiac injury or stress.


Assuntos
Coração/fisiologia , Homeostase , Macrófagos/fisiologia , Regeneração , Animais , Humanos , Inflamação , Macrófagos/imunologia , Miocárdio/imunologia
3.
Int J Mol Sci ; 22(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34360531

RESUMO

Cardiac diseases such as myocardial infarction (MI) can lead to adverse remodeling and impaired contractility of the heart due to widespread cardiomyocyte death in the damaged area. Current therapies focus on improving heart contractility and minimizing fibrosis with modest cardiac regeneration, but MI patients can still progress to heart failure (HF). There is a dire need for clinical therapies that can replace the lost myocardium, specifically by the induction of new myocyte formation from pre-existing cardiomyocytes. Many studies have shown terminally differentiated myocytes can re-enter the cell cycle and divide through manipulations of the cardiomyocyte cell cycle, signaling pathways, endogenous genes, and environmental factors. However, these approaches result in minimal myocyte renewal or cardiomegaly due to hyperactivation of cardiomyocyte proliferation. Finding the optimal treatment that will replenish cardiomyocyte numbers without causing tumorigenesis is a major challenge in the field. Another controversy is the inability to clearly define cardiomyocyte division versus myocyte DNA synthesis due to limited methods. In this review, we discuss several studies that induced cardiomyocyte cell cycle re-entry after cardiac injury, highlight whether cardiomyocytes completed cytokinesis, and address both limitations and methodological advances made to identify new myocyte formation.


Assuntos
Proliferação de Células , Cardiopatias/patologia , Coração/fisiologia , Miócitos Cardíacos/citologia , Animais , Diferenciação Celular , Humanos
4.
Theranostics ; 11(16): 7948-7969, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335973

RESUMO

Heart disease is the main cause of death worldwide. Because death of the myocardium is irreversible, it remains a significant clinical challenge to rescue myocardial deficiency. Cardiac tissue engineering (CTE) is a promising strategy for repairing heart defects and offers platforms for studying cardiac tissue. Numerous achievements have been made in CTE in the past decades based on various advanced engineering approaches. 3D bioprinting has attracted much attention due to its ability to integrate multiple cells within printed scaffolds with complex 3D structures, and many advancements in bioprinted CTE have been reported recently. Herein, we review the recent progress in 3D bioprinting for CTE. After a brief overview of CTE with conventional methods, the current 3D printing strategies are discussed. Bioink formulations based on various biomaterials are introduced, and strategies utilizing composite bioinks are further discussed. Moreover, several applications including heart patches, tissue-engineered cardiac muscle, and other bionic structures created via 3D bioprinting are summarized. Finally, we discuss several crucial challenges and present our perspective on 3D bioprinting techniques in the field of CTE.


Assuntos
Bioimpressão/métodos , Miocárdio/metabolismo , Engenharia Tecidual/métodos , Materiais Biocompatíveis/química , Biônica/métodos , Bioimpressão/tendências , Procedimentos Cirúrgicos Cardíacos/métodos , Coração/fisiologia , Cardiopatias/fisiopatologia , Cardiopatias/terapia , Humanos , Impressão Tridimensional/tendências , Tecidos Suporte/química
5.
Nat Biomed Eng ; 5(7): 749-758, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34272524

RESUMO

Stretchable wearable devices for the continuous monitoring of physiological signals from deep tissues are constrained by the depth of signal penetration and by difficulties in resolving signals from specific tissues. Here, we report the development and testing of a prototype skin-conformal ultrasonic phased array for the monitoring of haemodynamic signals from tissues up to 14 cm beneath the skin. The device allows for active focusing and steering of ultrasound beams over a range of incident angles so as to target regions of interest. In healthy volunteers, we show that the phased array can be used to monitor Doppler spectra from cardiac tissues, record central blood flow waveforms and estimate cerebral blood supply in real time. Stretchable and conformal skin-worn ultrasonic phased arrays may open up opportunities for wearable diagnostics.


Assuntos
Hemodinâmica/fisiologia , Monitorização Fisiológica/métodos , Circulação Cerebrovascular/fisiologia , Coração/fisiologia , Humanos , Análise em Microsséries , Monitorização Fisiológica/instrumentação , Razão Sinal-Ruído , Ultrassonografia Doppler , Dispositivos Eletrônicos Vestíveis
6.
Nat Genet ; 53(8): 1156-1165, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34211177

RESUMO

The most prevalent post-transcriptional mRNA modification, N6-methyladenosine (m6A), plays diverse RNA-regulatory roles, but its genetic control in human tissues remains uncharted. Here we report 129 transcriptome-wide m6A profiles, covering 91 individuals and 4 tissues (brain, lung, muscle and heart) from GTEx/eGTEx. We integrate these with interindividual genetic and expression variation, revealing 8,843 tissue-specific and 469 tissue-shared m6A quantitative trait loci (QTLs), which are modestly enriched in, but mostly orthogonal to, expression QTLs. We integrate m6A QTLs with disease genetics, identifying 184 GWAS-colocalized m6A QTL, including brain m6A QTLs underlying neuroticism, depression, schizophrenia and anxiety; lung m6A QTLs underlying expiratory flow and asthma; and muscle/heart m6A QTLs underlying coronary artery disease. Last, we predict novel m6A regulators that show preferential binding in m6A QTLs, protein interactions with known m6A regulators and expression correlation with the m6A levels of their targets. Our results provide important insights and resources for understanding both cis and trans regulation of epitranscriptomic modifications, their interindividual variation and their roles in human disease.


Assuntos
Adenosina/análogos & derivados , Encéfalo/fisiologia , Pulmão/fisiologia , Músculo Esquelético/fisiologia , Locos de Características Quantitativas , Adenosina/genética , Adenosina/metabolismo , Estudo de Associação Genômica Ampla , Coração/fisiologia , Humanos , Metilação , Especificidade de Órgãos , Polimorfismo de Nucleotídeo Único , Processamento Pós-Transcricional do RNA , Proteínas de Ligação a RNA/genética , Reprodutibilidade dos Testes
7.
Int J Mol Sci ; 22(14)2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34299159

RESUMO

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are proteins that contain highly conserved functional domains and sequence motifs that are correlated with their unique biophysical activities, to regulate cardiac pacemaker activity and synaptic transmission. These pacemaker proteins have been studied in mammalian species, but little is known now about their heart distribution in lower vertebrates and c-AMP modulation. Here, we characterized the pacemaker system in the heart of the wild Atlantic cod (Gadus morhua), with respect to primary pacemaker molecular markers. Special focus is given to the structural, ultrastructural and molecular characterization of the pacemaker domain, through the expression of HCN channel genes and the immunohistochemistry of HCN isoforms, including the location of intracardiac neurons that are adjacent to the sinoatrial region of the heart. Similarly to zebrafish and mammals, these neurons are immunoreactive to ChAT, VAChT and nNOS. It has been shown that cardiac pacemaking can be modulated by sympathetic and parasympathetic pathways, and the existence of intracardiac neurons projecting back to the central nervous system provide a plausible link between them.


Assuntos
Gadus morhua/metabolismo , Coração/fisiologia , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/química , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Ativação do Canal Iônico , Miócitos Cardíacos/metabolismo , Animais , Proteínas de Peixes/química , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Gadus morhua/genética , Gadus morhua/crescimento & desenvolvimento , Coração/inervação , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Miócitos Cardíacos/citologia , Isoformas de Proteínas , Transmissão Sináptica
8.
Aging (Albany NY) ; 13(13): 16938-16956, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34292877

RESUMO

Macrophage accumulation and nitrosative stress are known mechanisms underlying age-related cardiovascular pathology and functional decline. The cardiac muscle microenvironment is known to change with age, yet the direct effects of these changes have yet to be studied in-depth. The present study sought to better elucidate the role that biochemical and biomechanical alterations in cardiac tissue have in the altered phenotype and functionality of cardiac resident macrophages observed with increasing age. To accomplish this, naïve bone marrow derived macrophages from young mice were seeded onto either functionalized poly-dimethyl-siloxane hydrogels ranging in stiffness from 2kPA to 64kPA or onto tissue culture plastic, both of which were coated with either young or aged solubilized mouse cardiac extracellular matrix (cECM). Both biomechanical and biochemical alterations were found to have a significant effect on macrophage polarization and function. Increased substrate stiffness was found to promote macrophage morphologies associated with pro-inflammatory macrophage activation, increased expression of pro-inflammatory inducible nitric oxide synthase protein with increased nitric oxide secretion, and attenuated arginase activity and protein expression. Additionally, exposure to aged cECM promoted attenuated responsivity to both canonical pro-inflammatory and anti-inflammatory cytokine signaling cues when compared to young cECM treated cells. These results suggest that both biomechanical and biochemical changes in the cardiovascular system play a role in promoting the age-related shift towards pro-inflammatory macrophage populations associated with cardiovascular disease development.


Assuntos
Microambiente Celular/fisiologia , Coração/fisiologia , Macrófagos/fisiologia , Macrófagos/ultraestrutura , Envelhecimento/patologia , Envelhecimento/fisiologia , Animais , Arginase/metabolismo , Fenômenos Biomecânicos , Células da Medula Óssea , Citocinas/metabolismo , DNA/biossíntese , Ativação de Macrófagos , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/patologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/biossíntese , Fenótipo , Transdução de Sinais , Técnicas de Cultura de Tecidos
9.
J Cardiovasc Magn Reson ; 23(1): 86, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34193197

RESUMO

BACKGROUND: Cardiac evaluations, including cardiovascular magnetic resonance (CMR) imaging and biomarker results, are needed in children during mid-term recovery after infection with SARS-CoV-2. The incidence of CMR abnormalities 1-3 months after recovery is over 50% in older adults and has ranged between 1 and 15% in college athletes. Abnormal cardiac biomarkers are common in adults, even during recovery. METHODS: We performed CMR imaging in a prospectively-recruited pediatric cohort recovered from COVID-19 and multisystem inflammatory syndrome in children (MIS-C). We obtained CMR data and serum biomarkers. We compared these results to age-matched control patients, imaged prior to the SARS-CoV-2 pandemic. RESULTS: CMR was performed in 17 children (13.9 years, all ≤ 18 years) and 29 age-matched control patients without SARS-CoV-2 infection. Cases were recruited with symptomatic COVID-19 (11/17, 65%) or MIS-C (6/17, 35%) and studied an average of 2 months after diagnosis. All COVID-19 patients had been symptomatic with fever (73%), vomiting/diarrhea (64%), or breathing difficulty (55%) during infection. Left ventricular and right ventricular ejection fractions were indistinguishable between cases and controls (p = 0.66 and 0.70, respectively). Mean native global T1, global T2 values and segmental T2 maximum values were also not statistically different from control patients (p ≥ 0.06 for each). NT-proBNP and troponin levels were normal in all children. CONCLUSIONS: Children prospectively recruited following SARS-CoV-2 infection had normal CMR and cardiac biomarker evaluations during mid-term recovery. Trial Registration Not applicable.


Assuntos
COVID-19/complicações , Coração/diagnóstico por imagem , Coração/fisiologia , Imageamento por Ressonância Magnética/métodos , Síndrome de Resposta Inflamatória Sistêmica/complicações , Adolescente , Biomarcadores/sangue , COVID-19/sangue , Criança , Feminino , Humanos , Masculino , Estudos Prospectivos , SARS-CoV-2 , Síndrome de Resposta Inflamatória Sistêmica/sangue
10.
Cell Mol Life Sci ; 78(16): 6033-6049, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34274976

RESUMO

Melanocytes are pigmented cells residing mostly in the skin and hair follicles of vertebrates, where they contribute to colouration and protection against UV-B radiation. However, the spectrum of their functions reaches far beyond that. For instance, these pigment-producing cells are found inside the inner ear, where they contribute to the hearing function, and in the heart, where they are involved in the electrical conductivity and support the stiffness of cardiac valves. The embryonic origin of such extracutaneous melanocytes is not clear. We took advantage of lineage-tracing experiments combined with 3D visualizations and gene knockout strategies to address this long-standing question. We revealed that Schwann cell precursors are recruited from the local innervation during embryonic development and give rise to extracutaneous melanocytes in the heart, brain meninges, inner ear, and other locations. In embryos with a knockout of the EdnrB receptor, a condition imitating Waardenburg syndrome, we observed only nerve-associated melanoblasts, which failed to detach from the nerves and to enter the inner ear. Finally, we looked into the evolutionary aspects of extracutaneous melanocytes and found that pigment cells are associated mainly with nerves and blood vessels in amphibians and fish. This new knowledge of the nerve-dependent origin of extracutaneous pigment cells might be directly relevant to the formation of extracutaneous melanoma in humans.


Assuntos
Encéfalo/fisiologia , Orelha Interna/fisiologia , Coração/fisiologia , Meninges/fisiologia , Sistema Nervoso/fisiopatologia , Células de Schwann/fisiologia , Anfíbios/metabolismo , Anfíbios/fisiologia , Animais , Encéfalo/metabolismo , Linhagem da Célula/fisiologia , Orelha Interna/metabolismo , Desenvolvimento Embrionário/fisiologia , Feminino , Peixes/metabolismo , Peixes/fisiologia , Melanócitos/metabolismo , Melanócitos/fisiologia , Meninges/metabolismo , Camundongos , Sistema Nervoso/metabolismo , Gravidez , Receptor de Endotelina B/metabolismo , Células de Schwann/metabolismo
11.
Methods Mol Biol ; 2320: 285-293, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34302665

RESUMO

Myocardial infarction is caused by a lack of oxygen due to blockage of a coronary artery and is a common cause of heart failure. Despite therapeutic advances, the prognosis of patients with heart failure is poor. One of the reasons is that present therapeutic approaches do not restore the loss of cardiac tissue. Stem cell-based therapies have the potential to regenerate the myocardium, and numerous studies using stem cells have shown improved cardiac function and reduced infarct size. In this chapter, we describe our methodology for transplanting human induced pluripotent stem cell-derived cardiomyocytes into immunodeficient mouse hearts with myocardial infarction.


Assuntos
Células-Tronco Pluripotentes Induzidas/citologia , Miócitos Cardíacos/transplante , Animais , Modelos Animais de Doenças , Coração/fisiologia , Humanos , Injeções Intramusculares , Ligadura , Masculino , Camundongos , Camundongos Endogâmicos NOD , Infarto do Miocárdio/terapia , Regeneração , Respiração Artificial/métodos , Respiração Artificial/veterinária , Toracotomia/métodos , Toracotomia/veterinária
12.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299340

RESUMO

Unlike some lower vertebrates which can completely regenerate their heart, the human heart is a terminally differentiated organ. Cardiomyocytes lost during cardiac injury and heart failure cannot be replaced due to their limited proliferative capacity. Therefore, cardiac injury generally leads to progressive failure. Here, we summarize the latest progress in research on methods to induce cardiomyocyte cell cycle entry and heart repair through the alteration of cardiomyocyte plasticity, which is emerging as an effective strategy to compensate for the loss of functional cardiomyocytes and improve the impaired heart functions.


Assuntos
Proliferação de Células/fisiologia , Insuficiência Cardíaca/terapia , Miócitos Cardíacos/metabolismo , Animais , Ciclo Celular , Plasticidade Celular/genética , Plasticidade Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Coração/fisiologia , Insuficiência Cardíaca/fisiopatologia , Traumatismos Cardíacos/terapia , Humanos , Miócitos Cardíacos/fisiologia , Regeneração/fisiologia , Transdução de Sinais
13.
Genes Cells ; 26(8): 583-595, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34060165

RESUMO

Genetic mutations in actin regulators have been emerging as a cause of cardiomyopathy, although the functional link between actin dynamics and cardiac contraction remains largely unknown. To obtain insight into this issue, we examined the effects of pharmacological inhibition of formins, a major class of actin-assembling proteins. The formin inhibitor SMIFH2 significantly enhanced the cardiac contractility of isolated frog hearts, thereby augmenting cardiac performance. SMIFH2 treatment had no significant effects on the Ca2+ sensitivity of frog muscle fibers. Instead, it unexpectedly increased Ca2+ concentrations of isolated frog cardiomyocytes, suggesting that the inotropic effect is due to enhanced Ca2+ transients. In contrast to frog hearts, the contractility of mouse cardiomyocytes was attenuated by SMIFH2 treatment with decreasing Ca2+ transients. Thus, SMIFH2 has opposing effects on the Ca2+ transient and contractility between frog and mouse cardiomyocytes. We further found that SMIFH2 suppressed Ca2+ -release via type 2 ryanodine receptor (RyR2); this inhibitory effect may explain the species differences, since RyR2 is critical for Ca2+ transients in mouse myocardium but absent in frog myocardium. Although the mechanisms underlying the enhancement of Ca2+ transients in frog cardiomyocytes remain unclear, SMIFH2 differentially affects the cardiac contraction of amphibian and mammalian by differentially modulating their Ca2+ handling.


Assuntos
Sinalização do Cálcio , Coração/efeitos dos fármacos , Contração Miocárdica , Miócitos Cardíacos/efeitos dos fármacos , Animais , Células Cultivadas , Coração/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Rana catesbeiana , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Especificidade da Espécie , Tionas/farmacologia , Uracila/análogos & derivados , Uracila/farmacologia
14.
Methods Mol Biol ; 2276: 227-234, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34060045

RESUMO

In mitochondrial oxidative phosphorylation (Ox-Phos), individual electron transport chain complexes are thought to assemble into supramolecular entities termed supercomplexes (SCs). The technique of blue native (BN) gel electrophoresis has emerged as the method of choice for analyzing SCs. However, the process of sample extraction for BN gel analysis is somewhat tedious and introduces the possibility for experimental artifacts. Here we outline a streamlined method that eliminates a centrifugation step and provides a more representative sampling of a population of mitochondria on the final gel. Using this method, we show that SC composition does not appear to change dynamically with altered mitochondrial function.


Assuntos
Complexo de Proteínas da Cadeia de Transporte de Elétrons/análise , Coração/fisiologia , Mitocôndrias Cardíacas/química , Proteínas Mitocondriais/análise , Complexos Multiproteicos/análise , Miocárdio/química , Eletroforese em Gel de Poliacrilamida Nativa/métodos , Animais , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Camundongos , Mitocôndrias Cardíacas/metabolismo , Proteínas Mitocondriais/metabolismo , Complexos Multiproteicos/metabolismo , Miocárdio/metabolismo , Fosforilação Oxidativa
15.
Res Vet Sci ; 138: 137-147, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34144281

RESUMO

Histologically, the cardiac conduction network is formed of electrically isolated subendocardial fibers that comprise specialized cells with fewer myofibrils and mitochondria than cardiomyocytes. Our aim is to uncover regional variations of cardiac conduction fibers through histological and morphometric study in a porcine and human model. We analyzed five male adult human hearts and five male pig hearts. The left ventricles were dissected and sectioned in the axial plane into three parts: basal, middle third and apex regions. Cardiac conduction fibers study was carried out using hematoxylin-eosin and Masson's trichrome staining, and cardiac conduction cells and their junctions were identified using desmin, and a PAS method. Cardiac conduction fibers were difficult to pinpoint in humans, mostly showing a darker color or equal to cardiomyocytes. Cardiac conduction fibers in humans were in the subendocardium and in pigs in the myocardium and subendocardium. Cardiac conduction fibers were located mainly in the septal region in both humans and pigs. In our morphometric analysis, we were able to determine that cardiac conduction cells in humans (18.52 +/- 5.41 µm) and pigs (21.32 +/- 6.45 µm) were large, compared to cardiomyocytes. Conduction fiber-myocardial junctions were present in 10% in humans and 24.2% in pigs. The performance of immunohistochemical methods made it possible to improve the identification of cardiac conduction cells in the species studied. Study of cardiac conduction fibers and cells and their myocardial junctions is vital to gain insight into their normal distribution in the species analyzed, and thus advance the use of pigs in experimental models of the cardiac conduction system in humans.


Assuntos
Sistema de Condução Cardíaco/fisiologia , Ventrículos do Coração/citologia , Coração/fisiologia , Miocárdio/citologia , Sus scrofa/fisiologia , Animais , Sistema de Condução Cardíaco/citologia , Humanos , Masculino , Coloração e Rotulagem/veterinária
16.
J Zoo Wildl Med ; 52(2): 742-748, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34130421

RESUMO

Echocardiography is a noninvasive diagnostic tool that can provide instantaneous information about cardiac function, but it is uncommonly used by veterinarians to assess reptilian patients. Echocardiograms were performed on 14 clinically healthy, adult prairie rattlesnakes (Crotalus viridis), and cardiac measurements were taken in a horizontal and vertical position. Cardiac parameters including ventricular volume in systole and diastole, as well as the diameter of the left atrium, pulmonary artery, and paired left and right aortic arches were obtained. No evidence of cardiac disease was noted in any of the study animals. Males had a greater percentage of ventricular volume change (VVC) than females in the vertical position (P = 0.043). The percentage of ventricular volume change was significantly lower in the horizontal compared with the vertical position (P = 0.032) and was not different by sex. For the short-axis views, the right atrial diameter and short-axis ventricular area in diastole and systole were significantly smaller in snakes in the vertical compared with the horizontal position. This study is the first to obtain echocardiographic measurements in North American vipers and adds to the understanding of techniques used to evaluate the cardiac function of these species.


Assuntos
Crotalus/anatomia & histologia , Ecocardiografia/veterinária , Coração/anatomia & histologia , Animais , Feminino , Coração/fisiologia , Masculino
17.
Am J Physiol Heart Circ Physiol ; 321(1): H1-H14, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33989084

RESUMO

We tested the hypothesis that adiponectin deficiency attenuates cardiac and coronary microvascular function and prevents exercise training-induced adaptations of the myocardium and the coronary microvasculature in adult mice. Adult wild-type (WT) or adiponectin knockout (adiponectin KO) mice underwent treadmill exercise training or remained sedentary for 8-10 wk. Systolic and diastolic functions were assessed before and after exercise training or cage confinement. Vasoreactivity of coronary resistance arteries was assessed at the end of exercise training or cage confinement. Before exercise training, ejection fraction and fractional shortening were similar in adiponectin KO and WT mice, but isovolumic contraction time was significantly lengthened in adiponectin KO mice. Exercise training increased ejection fraction (12%) and fractional shortening (20%) with no change in isovolumic contraction time in WT mice. In adiponectin KO mice, both ejection fraction (-9%) and fractional shortening (-12%) were reduced after exercise training and these decreases were coupled to a further increase in isovolumic contraction time (20%). In sedentary mice, endothelium-dependent dilation to flow was higher in arterioles from adiponectin KO mice as compared with WT mice. Exercise training enhanced dilation to flow in WT mice but decreased flow-induced dilation in adiponectin KO mice. These data suggest that compensatory mechanisms contribute to the maintenance of cardiac and coronary microvascular function in sedentary mice lacking adiponectin; however, in the absence of adiponectin, cardiac and coronary microvascular adaptations to exercise training are compromised.NEW & NOTEWORTHY We report that compensatory mechanisms contribute to the maintenance of cardiac and coronary microvascular function in sedentary mice in which adiponectin has been deleted; however, when mice lacking adiponectin are subjected to the physiological stress of exercise training, beneficial coronary microvascular and cardiac adaptations are compromised or absent.


Assuntos
Adiponectina/genética , Coração/fisiologia , Condicionamento Físico Animal/fisiologia , Vasodilatação/fisiologia , Adiponectina/metabolismo , Animais , Endotélio Vascular/fisiopatologia , Masculino , Camundongos , Camundongos Knockout , Microvasos/fisiologia , Miocárdio/metabolismo
18.
Int J Mol Sci ; 22(9)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946248

RESUMO

Robust, spontaneous pacemaker activity originating in the sinoatrial node (SAN) of the heart is essential for cardiovascular function. Anatomical, electrophysiological, and molecular methods as well as mathematical modeling approaches have quite thoroughly characterized the transmembrane fluxes of Na+, K+ and Ca2+ that produce SAN action potentials (AP) and 'pacemaker depolarizations' in a number of different in vitro adult mammalian heart preparations. Possible ionic mechanisms that are responsible for SAN primary pacemaker activity are described in terms of: (i) a Ca2+-regulated mechanism based on a requirement for phasic release of Ca2+ from intracellular stores and activation of an inward current-mediated by Na+/Ca2+ exchange; (ii) time- and voltage-dependent activation of Na+ or Ca2+ currents, as well as a cyclic nucleotide-activated current, If; and/or (iii) a combination of (i) and (ii). Electrophysiological studies of single spontaneously active SAN myocytes in both adult mouse and rabbit hearts consistently reveal significant expression of a rapidly activating time- and voltage-dependent K+ current, often denoted IKr, that is selectively expressed in the leading or primary pacemaker region of the adult mouse SAN. The main goal of the present study was to examine by combined experimental and simulation approaches the functional or physiological roles of this K+ current in the pacemaker activity. Our patch clamp data of mouse SAN myocytes on the effects of a pharmacological blocker, E4031, revealed that a rapidly activating K+ current is essential for action potential (AP) repolarization, and its deactivation during the pacemaker potential contributes a small but significant component to the pacemaker depolarization. Mathematical simulations using a murine SAN AP model confirm that well known biophysical properties of a delayed rectifier K+ current can contribute to its role in generating spontaneous myogenic activity.


Assuntos
Canais de Potássio de Retificação Tardia/metabolismo , Miócitos Cardíacos/fisiologia , Potássio/metabolismo , Potenciais de Ação , Animais , Cátions Monovalentes/metabolismo , Células Cultivadas , Coração/fisiologia , Transporte de Íons , Camundongos , Modelos Cardiovasculares , Marca-Passo Artificial , Coelhos , Trocador de Sódio e Cálcio/metabolismo
19.
Nat Methods ; 18(5): 557-563, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33963344

RESUMO

Visualizing dynamic processes over large, three-dimensional fields of view at high speed is essential for many applications in the life sciences. Light-field microscopy (LFM) has emerged as a tool for fast volumetric image acquisition, but its effective throughput and widespread use in biology has been hampered by a computationally demanding and artifact-prone image reconstruction process. Here, we present a framework for artificial intelligence-enhanced microscopy, integrating a hybrid light-field light-sheet microscope and deep learning-based volume reconstruction. In our approach, concomitantly acquired, high-resolution two-dimensional light-sheet images continuously serve as training data and validation for the convolutional neural network reconstructing the raw LFM data during extended volumetric time-lapse imaging experiments. Our network delivers high-quality three-dimensional reconstructions at video-rate throughput, which can be further refined based on the high-resolution light-sheet images. We demonstrate the capabilities of our approach by imaging medaka heart dynamics and zebrafish neural activity with volumetric imaging rates up to 100 Hz.


Assuntos
Aprendizado Profundo , Coração/fisiologia , Processamento de Imagem Assistida por Computador/métodos , Microscopia/métodos , Animais , Fenômenos Biomecânicos , Cálcio/química , Larva/fisiologia , Oryzias/fisiologia , Reprodutibilidade dos Testes , Peixe-Zebra/fisiologia
20.
PLoS Biol ; 19(5): e3001200, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33999917

RESUMO

The heart develops from 2 sources of mesoderm progenitors, the first and second heart field (FHF and SHF). Using a single-cell transcriptomic assay combined with genetic lineage tracing and live imaging, we find the FHF and SHF are subdivided into distinct pools of progenitors in gastrulating mouse embryos at earlier stages than previously thought. Each subpopulation has a distinct origin in the primitive streak. The first progenitors to leave the primitive streak contribute to the left ventricle, shortly after right ventricle progenitor emigrate, followed by the outflow tract and atrial progenitors. Moreover, a subset of atrial progenitors are gradually incorporated in posterior locations of the FHF. Although cells allocated to the outflow tract and atrium leave the primitive streak at a similar stage, they arise from different regions. Outflow tract cells originate from distal locations in the primitive streak while atrial progenitors are positioned more proximally. Moreover, single-cell RNA sequencing demonstrates that the primitive streak cells contributing to the ventricles have a distinct molecular signature from those forming the outflow tract and atrium. We conclude that cardiac progenitors are prepatterned within the primitive streak and this prefigures their allocation to distinct anatomical structures of the heart. Together, our data provide a new molecular and spatial map of mammalian cardiac progenitors that will support future studies of heart development, function, and disease.


Assuntos
Linhagem da Célula/genética , Coração/embriologia , Linha Primitiva/embriologia , Animais , Linhagem da Célula/fisiologia , Feminino , Gástrula , Expressão Gênica/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Coração/fisiologia , Átrios do Coração/embriologia , Ventrículos do Coração/embriologia , Masculino , Mesoderma , Camundongos , Camundongos Endogâmicos C57BL , Morfogênese , Linha Primitiva/fisiologia , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos
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