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1.
Artigo em Inglês | MEDLINE | ID: mdl-34639493

RESUMO

Mercury (Hg) contamination in the Gulf of Trieste (northern Adriatic Sea) due to mining activity in Idrija (Slovenia) still represents an issue of environmental concern. The Isonzo/Soca River's freshwater inputs have been identified as the main source of Hg into the Gulf, especially following periods of medium-high discharge. This research aims to evaluate the occurrence and distribution of dissolved (DHg) and particulate (PHg) Hg along the water column in the northernmost sector of the Gulf, a shallow and sheltered embayment suitable for the accumulation of fine sediments. Sediment and water samples were collected under unperturbed and perturbed environmental conditions induced by natural and anthropogenic factors. Mercury in the sediments (0.77-6.39 µg g-1) and its relationship to grain size were found to be consistent with previous research focused on the entire Gulf, testifying to the common origin of the sediment. Results showed a notable variability of DHg (

Assuntos
Mercúrio , Poluentes Químicos da Água , Monitoramento Ambiental , Sedimentos Geológicos , Mercúrio/análise , Mineração , Rios , Água , Poluentes Químicos da Água/análise
2.
Bull Environ Contam Toxicol ; 106(6): 942-948, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33655405

RESUMO

The sediments in the Gulf of Trieste (northern Adriatic Sea, Italy) are contaminated by mercury (Hg) due to historic mining which took place in Idrija (Slovenia). Despite many studies having been done regarding Hg, no information is available on the potential impact of dredging required along the main channel approaching the Port of Monfalcone. Sixteen surface sediment samples were collected along the channel to determine both total Hg concentration and chemical species using the thermo-desorption (TD) technique. Six samples were also chosen to apply a selective sequential extraction (SSE). The TD technique showed the maximum Hg release approximately at 260 and 335°C, corresponding to metacinnabar (ß-HgS) and cinnabar (α-HgS), respectively. The SSE demonstrated that Hg was mainly associated with poorly soluble or insoluble compounds (98.7%). A resuspension event over a limited period of time can be considered of negligible impact to the water column due to the scarce Hg mobility from sediments.


Assuntos
Mercúrio , Poluentes Químicos da Água , Monitoramento Ambiental , Sedimentos Geológicos , Itália , Mercúrio/análise , Eslovênia , Poluentes Químicos da Água/análise
3.
Biomed Signal Process Control ; 51: 30-41, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31938034

RESUMO

The profile of the action potential (AP) of cardiomyocytes contributes to the modality of ventricular repolarization of the heart. Experimentally, the examination of the AP in isolated cardiomyocytes provides information on their electrical properties, adaptations to physiological and pathological conditions, and putative ionic mechanisms involved in the process. Currently, there are no available platforms for automated assessment of AP properties and standard methodologies restrict the examination of the AP repolarization to discrete, user-defined ranges, neglecting significant intervals of the electrical recovery. This study proposes two automatic methods to assess AP profile throughout the entire repolarization phase. One method is based on AP data inversion and direct extraction of patterns describing beat-to-beat dynamics. The second method is based on evolutive singular value decomposition (ESVD), which identifies common patterns in a series of consecutive APs. The two methodologies were employed to analyze electrical signals collected from cardiomyocites obtained from healthy mice and animals with diabetes, a condition associated with alterations of AP properties in cardiac cells. Our methodologies revealed that the duration of the early repolarization phase of the AP tended to become progressively longer during a stimulation train, whereas the late repolarization progressively shortened. Although this behavior was comparable in the two groups of cells, alterations in AP dynamics occurred at distinct repolarization levels, a feature highlighted by the ESVD approach. In conclusion, the proposed methodologies allow detailed, automatic analysis of the AP repolarization and identification of critical alterations occurring in the electrical behavior of myocytes under pathological conditions.

4.
Am J Physiol Heart Circ Physiol ; 314(1): H68-H81, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-28939651

RESUMO

Notch receptor signaling is active during cardiac development and silenced in myocytes after birth. Conversely, outward K+ Kv currents progressively appear in postnatal myocytes leading to shortening of the action potential (AP) and acquisition of the mature electrical phenotype. In the present study, we tested the possibility that Notch signaling modulates the electrical behavior of cardiomyocytes by interfering with Kv currents. For this purpose, the effects of Notch receptor activity on electrophysiological properties of myocytes were evaluated using transgenic mice with inducible expression of the Notch1 intracellular domain (NICD), the functional fragment of the activated Notch receptor, and in neonatal myocytes after inhibition of the Notch transduction pathway. By patch clamp, NICD-overexpressing cells presented prolonged AP duration and reduced upstroke amplitude, properties that were coupled with reduced rapidly activating Kv and fast Na+ currents, compared with cells obtained from wild-type mice. In cultured neonatal myocytes, inhibition of the proteolitic release of NICD with a γ-secretase antagonist increased transcript levels of the Kv channel-interacting proteins 2 (KChIP2) and enhanced the density of Kv currents. Collectively, these results indicate that Notch signaling represents an important regulator of the electrophysiological behavior of developing and adult myocytes by repressing, at least in part, repolarizing Kv currents. NEW & NOTEWORTHY We investigated the effects of Notch receptor signaling on the electrical properties of cardiomyocytes. Our results indicate that the Notch transduction pathway interferes with outward K+ Kv currents, critical determinants of the electrical repolarization of myocytes.


Assuntos
Miócitos Cardíacos/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Potássio/metabolismo , Receptor Notch1/metabolismo , Transdução de Sinais , Animais , Células Cultivadas , Feminino , Cinética , Proteínas Interatuantes com Canais de Kv/genética , Proteínas Interatuantes com Canais de Kv/metabolismo , Masculino , Potenciais da Membrana , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Receptor Notch1/genética , Sódio/metabolismo
5.
NPJ Regen Med ; 2: 27, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29302361

RESUMO

The plasticity of c-kit-positive bone marrow cells (c-kit-BMCs) in tissues different from their organ of origin remains unclear. We tested the hypothesis that c-kit-BMCs are functionally heterogeneous and only a subgroup of these cells possesses cardiomyogenic potential. Population-based assays fall short of identifying the properties of individual stem cells, imposing on us the introduction of single cell-based approaches to track the fate of c-kit-BMCs in the injured heart; they included viral gene-tagging, multicolor clonal-marking and transcriptional profiling. Based on these strategies, we report that single mouse c-kit-BMCs expand clonally within the infarcted myocardium and differentiate into specialized cardiac cells. Newly-formed cardiomyocytes, endothelial cells, fibroblasts and c-kit-BMCs showed in their genome common sites of viral integration, providing strong evidence in favor of the plasticity of a subset of BMCs expressing the c-kit receptor. Similarly, individual c-kit-BMCs, which were infected with multicolor reporters and injected in infarcted hearts, formed cardiomyocytes and vascular cells organized in clusters of similarly colored cells. The uniform distribution of fluorescent proteins in groups of specialized cells documented the polyclonal nature of myocardial regeneration. The transcriptional profile of myogenic c-kit-BMCs and whole c-kit-BMCs was defined by RNA sequencing. Genes relevant for engraftment, survival, migration, and differentiation were enriched in myogenic c-kit-BMCs, a cell subtype which could not be assigned to a specific hematopoietic lineage. Collectively, our findings demonstrate that the bone marrow comprises a category of cardiomyogenic, vasculogenic and/or fibrogenic c-kit-positive cells and a category of c-kit-positive cells that retains an undifferentiated state within the damaged heart.

6.
Am J Physiol Heart Circ Physiol ; 312(1): H150-H161, 2017 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-27881388

RESUMO

Diabetes and other metabolic conditions characterized by elevated blood glucose constitute important risk factors for cardiovascular disease. Hyperglycemia targets myocardial cells rendering ineffective mechanical properties of the heart, but cellular alterations dictating the progressive deterioration of cardiac function with metabolic disorders remain to be clarified. In the current study, we examined the effects of hyperglycemia on cardiac function and myocyte physiology by employing mice with high blood glucose induced by administration of streptozotocin, a compound toxic to insulin-producing ß-cells. We found that hyperglycemia initially delayed the electrical recovery of the heart, whereas cardiac function became defective only after ~2 mo with this condition and gradually worsened with time. Prolonged hyperglycemia was associated with increased chamber dilation, thinning of the left ventricle (LV), and myocyte loss. Cardiomyocytes from hyperglycemic mice exhibited defective Ca2+ transients before the appearance of LV systolic defects. Alterations in Ca2+ transients involved enhanced spontaneous Ca2+ releases from the sarcoplasmic reticulum (SR), reduced cytoplasmic Ca2+ clearance, and declined SR Ca2+ load. These defects have important consequences on myocyte contraction, relaxation, and mechanisms of rate adaptation. Collectively, our data indicate that hyperglycemia alters intracellular Ca2+ homeostasis in cardiomyocytes, hindering contractile activity and contributing to the manifestation of the diabetic cardiomyopathy. NEW & NOTEWORTHY: We have investigated the effects of hyperglycemia on cardiomyocyte physiology and ventricular function. Our results indicate that defective Ca2+ handling is a critical component of the progressive deterioration of cardiac performance of the diabetic heart.


Assuntos
Cálcio/metabolismo , Diabetes Mellitus Experimental/metabolismo , Homeostase , Hiperglicemia/metabolismo , Miócitos Cardíacos/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia , Potenciais de Ação , Animais , Cafeína/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Diabetes Mellitus Experimental/complicações , Ecocardiografia , Eletrocardiografia , Feminino , Preparação de Coração Isolado , Masculino , Camundongos , Miócitos Cardíacos/efeitos dos fármacos , Técnicas de Patch-Clamp , Retículo Sarcoplasmático/efeitos dos fármacos , Retículo Sarcoplasmático/metabolismo , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/etiologia
7.
J Am Heart Assoc ; 5(2)2016 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-26896476

RESUMO

BACKGROUND: Diabetes is associated with prolongation of the QT interval of the electrocardiogram and enhanced dispersion of ventricular repolarization, factors that, together with atherosclerosis and myocardial ischemia, may promote the occurrence of electrical disorders. Thus, we tested the possibility that alterations in transmembrane ionic currents reduce the repolarization reserve of myocytes, leading to action potential (AP) prolongation and enhanced beat-to-beat variability of repolarization. METHODS AND RESULTS: Diabetes was induced in mice with streptozotocin (STZ), and effects of hyperglycemia on electrical properties of whole heart and myocytes were studied with respect to an untreated control group (Ctrl) using electrocardiographic recordings in vivo, ex vivo perfused hearts, and single-cell patch-clamp analysis. Additionally, a newly developed algorithm was introduced to obtain detailed information of the impact of high glucose on AP profile. Compared to Ctrl, hyperglycemia in STZ-treated animals was coupled with prolongation of the QT interval, enhanced temporal dispersion of electrical recovery, and susceptibility to ventricular arrhythmias, defects observed, in part, in the Akita mutant mouse model of type I diabetes. AP was prolonged and beat-to-beat variability of repolarization was enhanced in diabetic myocytes, with respect to Ctrl cells. Density of Kv K(+) and L-type Ca(2+) currents were decreased in STZ myocytes, in comparison to cells from normoglycemic mice. Pharmacological reduction of Kv currents in Ctrl cells lengthened AP duration and increased temporal dispersion of repolarization, reiterating features identified in diabetic myocytes. CONCLUSIONS: Reductions in the repolarizing K(+) currents may contribute to electrical disturbances of the diabetic heart.


Assuntos
Potenciais de Ação , Algoritmos , Arritmias Cardíacas/etiologia , Diabetes Mellitus Experimental/complicações , Cardiomiopatias Diabéticas/etiologia , Frequência Cardíaca , Miócitos Cardíacos/metabolismo , Canais de Potássio/metabolismo , Potássio/metabolismo , Animais , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/fisiopatologia , Eletrocardiografia , Feminino , Cinética , Masculino , Camundongos Endogâmicos C57BL , Técnicas de Patch-Clamp , Processamento de Sinais Assistido por Computador
8.
Am J Physiol Heart Circ Physiol ; 310(7): H873-90, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-26801307

RESUMO

Studies of myocardial aging are complex and the mechanisms involved in the deterioration of ventricular performance and decreased functional reserve of the old heart remain to be properly defined. We have studied a colony of beagle dogs from 3 to 14 yr of age kept under a highly regulated environment to define the effects of aging on the myocardium. Ventricular, myocardial, and myocyte function, together with anatomical and structural properties of the organ and cardiomyocytes, were evaluated. Ventricular hypertrophy was not observed with aging and the structural composition of the myocardium was modestly affected. Alterations in the myocyte compartment were identified in aged dogs, and these factors negatively interfere with the contractile reserve typical of the young heart. The duration of the action potential is prolonged in old cardiomyocytes contributing to the slower electrical recovery of the myocardium. Also, the remodeled repolarization of cardiomyocytes with aging provides inotropic support to the senescent muscle but compromises its contractile reserve, rendering the old heart ineffective under conditions of high hemodynamic demand. The defects in the electrical and mechanical properties of cardiomyocytes with aging suggest that this cell population is an important determinant of the cardiac senescent phenotype. Collectively, the delayed electrical repolarization of aging cardiomyocytes may be viewed as a critical variable of the aging myopathy and its propensity to evolve into ventricular decompensation under stressful conditions.


Assuntos
Potenciais de Ação , Envelhecimento/fisiologia , Miócitos Cardíacos/fisiologia , Função Ventricular , Animais , Cães , Feminino , Hemodinâmica , Masculino
9.
Nat Commun ; 6: 8803, 2015 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-26541940

RESUMO

The aging myopathy manifests itself with diastolic dysfunction and preserved ejection fraction. We raised the possibility that, in a mouse model of physiological aging, defects in electromechanical properties of cardiomyocytes are important determinants of the diastolic characteristics of the myocardium, independently from changes in structural composition of the muscle and collagen framework. Here we show that an increase in the late Na(+) current (INaL) in aging cardiomyocytes prolongs the action potential (AP) and influences temporal kinetics of Ca(2+) cycling and contractility. These alterations increase force development and passive tension. Inhibition of INaL shortens the AP and corrects dynamics of Ca(2+) transient, cell contraction and relaxation. Similarly, repolarization and diastolic tension of the senescent myocardium are partly restored. Thus, INaL offers inotropic support, but negatively interferes with cellular and ventricular compliance, providing a new perspective of the biology of myocardial aging and the aetiology of the defective cardiac performance in the elderly.


Assuntos
Potenciais de Ação , Envelhecimento/metabolismo , Cálcio/metabolismo , Cardiomiopatias/metabolismo , Ventrículos do Coração/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Retículo Sarcoplasmático/metabolismo , Sódio/metabolismo , Animais , Cardiomiopatias/fisiopatologia , Colágeno , Modelos Animais de Doenças , Coração/fisiopatologia , Ventrículos do Coração/fisiopatologia , Camundongos , Camundongos Knockout , Contração Miocárdica , Técnicas de Patch-Clamp , Subunidade beta-1 do Canal de Sódio Disparado por Voltagem/genética , Subunidade beta-1 do Canal de Sódio Disparado por Voltagem/metabolismo
11.
Circ Res ; 114(1): 41-55, 2014 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-24170267

RESUMO

RATIONALE: Hypoxia favors stem cell quiescence, whereas normoxia is required for stem cell activation, but whether cardiac stem cell (CSC) function is regulated by the hypoxic/normoxic state of the cell is currently unknown. OBJECTIVE: A balance between hypoxic and normoxic CSCs may be present in the young heart, although this homeostatic control may be disrupted with aging. Defects in tissue oxygenation occur in the old myocardium, and this phenomenon may expand the pool of hypoxic CSCs, which are no longer involved in myocyte renewal. METHODS AND RESULTS: Here, we show that the senescent heart is characterized by an increased number of quiescent CSCs with intact telomeres that cannot re-enter the cell cycle and form a differentiated progeny. Conversely, myocyte replacement is controlled only by frequently dividing CSCs with shortened telomeres; these CSCs generate a myocyte population that is chronologically young but phenotypically old. Telomere dysfunction dictates their actual age and mechanical behavior. However, the residual subset of quiescent young CSCs can be stimulated in situ by stem cell factor reversing the aging myopathy. CONCLUSIONS: Our findings support the notion that strategies targeting CSC activation and growth interfere with the manifestations of myocardial aging in an animal model. Although caution has to be exercised in the translation of animal studies to human beings, our data strongly suggest that a pool of functionally competent CSCs persists in the senescent heart and that this stem cell compartment can promote myocyte regeneration effectively, partly correcting the aging myopathy.


Assuntos
Envelhecimento/efeitos dos fármacos , Cardiomiopatias/metabolismo , Hipóxia/metabolismo , Mioblastos Cardíacos/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Fator de Células-Tronco/farmacologia , Nicho de Células-Tronco , Envelhecimento/metabolismo , Animais , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/patologia , Ciclo Celular , Linhagem da Célula , Proliferação de Células , Senescência Celular/efeitos dos fármacos , Hipóxia/patologia , Camundongos , Camundongos Endogâmicos C57BL , Mioblastos Cardíacos/efeitos dos fármacos , Mioblastos Cardíacos/fisiologia , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Fator de Células-Tronco/uso terapêutico , Homeostase do Telômero
12.
Circulation ; 128(20): 2211-23, 2013 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-24141256

RESUMO

BACKGROUND: Aging negatively impacts on the function of resident human cardiac progenitor cells (hCPCs). Effective regeneration of the injured heart requires mobilization of hCPCs to the sites of damage. In the young heart, signaling by the guidance receptor EphA2 in response to the ephrin A1 ligand promotes hCPC motility and improves cardiac recovery after infarction. METHODS AND RESULTS: We report that old hCPCs are characterized by cell-autonomous inhibition of their migratory ability ex vivo and impaired translocation in vivo in the damaged heart. EphA2 expression was not decreased in old hCPCs; however, the elevated level of reactive oxygen species in aged cells induced post-translational modifications of the EphA2 protein. EphA2 oxidation interfered with ephrin A1-stimulated receptor auto-phosphorylation, activation of Src family kinases, and caveolin-1-mediated internalization of the receptor. Cellular aging altered the EphA2 endocytic route, affecting the maturation of EphA2-containing endosomes and causing premature signal termination. Overexpression of functionally intact EphA2 in old hCPCs corrected the defects in endocytosis and downstream signaling, enhancing cell motility. Based on the ability of phenotypically young hCPCs to respond efficiently to ephrin A1, we developed a novel methodology for the prospective isolation of live hCPCs with preserved migratory capacity and growth reserve. CONCLUSIONS: Our data demonstrate that the ephrin A1/EphA2 pathway may serve as a target to facilitate trafficking of hCPCs in the senescent myocardium. Importantly, EphA2 receptor function can be implemented for the selection of hCPCs with high therapeutic potential, a clinically relevant strategy that does not require genetic manipulation of stem cells.


Assuntos
Células-Tronco Adultas/fisiologia , Envelhecimento/fisiologia , Movimento Celular/fisiologia , Miocárdio/citologia , Receptor EphA2/metabolismo , Transdução de Sinais/fisiologia , Adulto , Células-Tronco Adultas/citologia , Idoso , Células Cultivadas , Endocitose/fisiologia , Efrina-A1/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptor EphA2/genética , Regeneração/fisiologia , Transferrina/metabolismo
13.
Circulation ; 128(12): 1286-97, 2013 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-23983250

RESUMO

BACKGROUND: Little is known about the function of inositol 1,4,5-trisphosphate receptors (IP3Rs) in the adult heart experimentally. Moreover, whether these Ca(2+) release channels are present and play a critical role in human cardiomyocytes remains to be defined. IP3Rs may be activated after Gαq-protein-coupled receptor stimulation, affecting Ca(2+) cycling, enhancing myocyte performance, and potentially favoring an increase in the incidence of arrhythmias. METHODS AND RESULTS: IP3R function was determined in human left ventricular myocytes, and this analysis was integrated with assays in mouse myocytes to identify the mechanisms by which IP3Rs influence the electric and mechanical properties of the myocardium. We report that IP3Rs are expressed and operative in human left ventricular myocytes. After Gαq-protein-coupled receptor activation, Ca(2+) mobilized from the sarcoplasmic reticulum via IP3Rs contributes to the decrease in resting membrane potential, prolongation of the action potential, and occurrence of early afterdepolarizations. Ca(2+) transient amplitude and cell shortening are enhanced, and extrasystolic and dysregulated Ca(2+) elevations and contractions become apparent. These alterations in the electromechanical behavior of human cardiomyocytes are coupled with increased isometric twitch of the myocardium and arrhythmic events, suggesting that Gαq-protein-coupled receptor activation provides inotropic reserve, which is hampered by electric instability and contractile abnormalities. Additionally, our findings support the notion that increases in Ca(2+) load by IP3Rs promote Ca(2+) extrusion by forward-mode Na(+)/Ca(2+) exchange, an important mechanism of arrhythmic events. CONCLUSIONS: The Gαq-protein/coupled receptor/IP3R axis modulates the electromechanical properties of the human myocardium and its propensity to develop arrhythmias.


Assuntos
Potenciais de Ação/fisiologia , Sinalização do Cálcio/fisiologia , Insuficiência Cardíaca/fisiopatologia , Receptores de Inositol 1,4,5-Trifosfato/fisiologia , Miócitos Cardíacos/fisiologia , Adulto , Animais , Arritmias Cardíacas/fisiopatologia , Células Cultivadas , Feminino , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/fisiologia , Insuficiência Cardíaca/genética , Ventrículos do Coração/citologia , Humanos , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Contração Miocárdica/fisiologia , Miócitos Cardíacos/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/fisiologia , Retículo Sarcoplasmático/fisiologia , Transdução de Sinais/fisiologia
14.
Circulation ; 126(15): 1869-81, 2012 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-22955965

RESUMO

BACKGROUND: Two opposite views of cardiac growth are currently held; one views the heart as a static organ characterized by a large number of cardiomyocytes that are present at birth and live as long as the organism, and the other views the heart a highly plastic organ in which the myocyte compartment is restored several times during the course of life. METHODS AND RESULTS: The average age of cardiomyocytes, vascular endothelial cells (ECs), and fibroblasts and their turnover rates were measured by retrospective (14)C birth dating of cells in 19 normal hearts 2 to 78 years of age and in 17 explanted failing hearts 22 to 70 years of age. We report that the human heart is characterized by a significant turnover of ventricular myocytes, ECs, and fibroblasts, physiologically and pathologically. Myocyte, EC, and fibroblast renewal is very high shortly after birth, decreases during postnatal maturation, remains relatively constant in the adult organ, and increases dramatically with age. From 20 to 78 years of age, the adult human heart entirely replaces its myocyte, EC, and fibroblast compartment ≈8, ≈6, and ≈8 times, respectively. Myocyte, EC, and fibroblast regeneration is further enhanced with chronic heart failure. CONCLUSIONS: The human heart is a highly dynamic organ that retains a remarkable degree of plasticity throughout life and in the presence of chronic heart failure. However, the ability to regenerate cardiomyocytes, vascular ECs, and fibroblasts cannot prevent the manifestations of myocardial aging or oppose the negative effects of ischemic and idiopathic dilated cardiomyopathy.


Assuntos
Insuficiência Cardíaca/fisiopatologia , Desenvolvimento Muscular/fisiologia , Miócitos Cardíacos/fisiologia , Adolescente , Adulto , Idoso , Envelhecimento , Criança , Pré-Escolar , Células Endoteliais/fisiologia , Fibroblastos/fisiologia , Coração/fisiologia , Humanos , Pessoa de Meia-Idade , Miócitos Cardíacos/citologia , Regeneração , Doadores de Tecidos , Adulto Jovem
15.
Circ Res ; 110(5): 701-15, 2012 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-22275487

RESUMO

RATIONALE: Embryonic and fetal myocardial growth is characterized by a dramatic increase in myocyte number, but whether the expansion of the myocyte compartment is dictated by activation and commitment of resident cardiac stem cells (CSCs), division of immature myocytes or both is currently unknown. OBJECTIVE: In this study, we tested whether prenatal cardiac development is controlled by activation and differentiation of CSCs and whether division of c-kit-positive CSCs in the mouse heart is triggered by spontaneous Ca(2+) oscillations. METHODS AND RESULTS: We report that embryonic-fetal c-kit-positive CSCs are self-renewing, clonogenic and multipotent in vitro and in vivo. The growth and commitment of c-kit-positive CSCs is responsible for the generation of the myocyte progeny of the developing heart. The close correspondence between values computed by mathematical modeling and direct measurements of myocyte number at E9, E14, E19 and 1 day after birth strongly suggests that the organogenesis of the embryonic heart is dependent on a hierarchical model of cell differentiation regulated by resident CSCs. The growth promoting effects of c-kit-positive CSCs are triggered by spontaneous oscillations in intracellular Ca(2+), mediated by IP3 receptor activation, which condition asymmetrical stem cell division and myocyte lineage specification. CONCLUSIONS: Myocyte formation derived from CSC differentiation is the major determinant of cardiac growth during development. Division of c-kit-positive CSCs in the mouse is promoted by spontaneous Ca(2+) spikes, which dictate the pattern of stem cell replication and the generation of a myocyte progeny at all phases of prenatal life and up to one day after birth.


Assuntos
Diferenciação Celular/fisiologia , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Coração/embriologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/fisiologia , Proteínas Proto-Oncogênicas c-kit/metabolismo , Animais , Cálcio/metabolismo , Sinalização do Cálcio/fisiologia , Células Cultivadas , Técnicas de Cultura Embrionária , Receptores de Inositol 1,4,5-Trifosfato/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Animais , Modelos Teóricos , Organogênese/fisiologia , Proteínas Proto-Oncogênicas c-kit/genética
16.
Am J Pathol ; 179(1): 349-66, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21703415

RESUMO

Currently, it is unknown whether defects in stem cell growth and differentiation contribute to myocardial aging and chronic heart failure (CHF), and whether a compartment of functional human cardiac stem cells (hCSCs) persists in the decompensated heart. To determine whether aging and CHF are critical determinants of the loss in growth reserve of the heart, the properties of hCSCs were evaluated in 18 control and 23 explanted hearts. Age and CHF showed a progressive decrease in functionally competent hCSCs. Chronological age was a major predictor of five biomarkers of hCSC senescence: telomeric shortening, attenuated telomerase activity, telomere dysfunction-induced foci, and p21(Cip1) and p16(INK4a) expression. CHF had similar consequences for hCSCs, suggesting that defects in the balance between cardiomyocyte mass and the pool of nonsenescent hCSCs may condition the evolution of the decompensated myopathy. A correlation was found previously between telomere length in circulating bone marrow cells and cardiovascular diseases, but that analysis was restricted to average telomere length in a cell population, neglecting the fact that telomere attrition does not occur uniformly in all cells. The present study provides the first demonstration that dysfunctional telomeres in hCSCs are biomarkers of aging and heart failure. The biomarkers of cellular senescence identified here can be used to define the birth date of hCSCs and to sort young cells with potential therapeutic efficacy.


Assuntos
Senescência Celular , Insuficiência Cardíaca/complicações , Coração/fisiopatologia , Miócitos Cardíacos/patologia , Células-Tronco/citologia , Células-Tronco/fisiologia , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Western Blotting , Estudos de Casos e Controles , Diferenciação Celular , Proliferação de Células , Feminino , Imunofluorescência , Perfilação da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias Experimentais/etiologia , Neoplasias Experimentais/patologia , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Telomerase , Telômero/genética
17.
Circ Res ; 108(9): 1071-83, 2011 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-21415392

RESUMO

RATIONALE: Understanding the mechanisms that regulate trafficking of human cardiac stem cells (hCSCs) may lead to development of new therapeutic approaches for the failing heart. OBJECTIVE: We tested whether the motility of hCSCs in immunosuppressed infarcted animals is controlled by the guidance system that involves the interaction of Eph receptors with ephrin ligands. METHODS AND RESULTS: Within the cardiac niches, cardiomyocytes expressed preferentially the ephrin A1 ligand, whereas hCSCs possessed the EphA2 receptor. Treatment of hCSCs with ephrin A1 resulted in the rapid internalization of the ephrin A1-EphA2 complex, posttranslational modifications of Src kinases, and morphological changes consistent with the acquisition of a motile cell phenotype. Ephrin A1 enhanced the motility of hCSCs in vitro, and their migration in vivo following acute myocardial infarction. At 2 weeks after infarction, the volume of the regenerated myocardium was 2-fold larger in animals injected with ephrin A1-activated hCSCs than in animals receiving control hCSCs; this difference was dictated by a greater number of newly formed cardiomyocytes and coronary vessels. The increased recovery in myocardial mass with ephrin A1-treated hCSCs was characterized by further restoration of cardiac function and by a reduction in arrhythmic events. CONCLUSIONS: Ephrin A1 promotes the motility of EphA2-positive hCSCs, facilitates their migration to the area of damage, and enhances cardiac repair. Thus, in situ stimulation of resident hCSCs with ephrin A1 or their ex vivo activation before myocardial delivery improves cell targeting to sites of injury, possibly providing a novel strategy for the management of the diseased heart.


Assuntos
Efrina-A1/genética , Efrina-A2/genética , Células-Tronco Hematopoéticas/citologia , Infarto do Miocárdio/fisiopatologia , Miócitos Cardíacos/citologia , Animais , Adesão Celular/fisiologia , Membrana Celular/metabolismo , Movimento Celular/fisiologia , Citoplasma/metabolismo , Efrina-A1/metabolismo , Efrina-A2/metabolismo , Expressão Gênica/fisiologia , Proteínas de Fluorescência Verde/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Infarto do Miocárdio/patologia , Infarto do Miocárdio/terapia , Ratos , Ratos Endogâmicos F344 , Taquicardia Ventricular/patologia , Taquicardia Ventricular/fisiopatologia , Taquicardia Ventricular/terapia
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