RESUMO
Diabetes mellitus is one of the prime risk factors for cardiovascular complications and is linked with high morbidity and mortality. Diabetic cardiomyopathy (DCM) often manifests as reduced cardiac contractility, myocardial fibrosis, diastolic dysfunction, and chronic heart failure. Inflammation, changes in calcium (Ca2+) handling and cardiomyocyte loss are often implicated in the development and progression of DCM. Although the existence of DCM was established nearly four decades ago, the exact mechanisms underlying this disease pathophysiology is constantly evolving. Furthermore, the complex pathophysiology of DCM is linked with exosomes, which has recently shown to facilitate intercellular (cell-to-cell) communication through biomolecules such as micro RNA (miRNA), proteins, enzymes, cell surface receptors, growth factors, cytokines, and lipids. Inflammatory response and Ca2+ signaling are interrelated and DCM has been known to adversely affect many of these signaling molecules either qualitatively and/or quantitatively. In this literature review, we have demonstrated that Ca2+ regulators are tightly controlled at different molecular and cellular levels during various biological processes in the heart. Inflammatory mediators, miRNA and exosomes are shown to interact with these regulators, however how these mediators are linked to Ca2+ handling during DCM pathogenesis remains elusive. Thus, further investigations are needed to understand the mechanisms to restore cardiac Ca2+ homeostasis and function, and to serve as potential therapeutic targets in the treatment of DCM.
Assuntos
Cálcio , Diabetes Mellitus , Cardiomiopatias Diabéticas , Exossomos , MicroRNAs , Humanos , Cardiomiopatias Diabéticas/metabolismo , Exossomos/metabolismo , Inflamação/complicações , MicroRNAs/genética , Miócitos Cardíacos/metabolismo , Cálcio/metabolismoRESUMO
PURPOSE: This post-hoc analysis examined whether age modified the efficacy and safety of alirocumab, a PCSK9 inhibitor, in patients with heterozygous familial hypercholesterolemia (HeFH), using pooled data from four 78-week placebo-controlled phase 3 trials (ODYSSEY FH I, FH II, LONG TERM, and HIGH FH). METHODS: Data from 1257 patients with HeFH on maximally tolerated statin ± other lipid-lowering therapies were analyzed by an alirocumab dose regimen and by age subgroups (18 to < 45, 45 to < 55, 55 to < 65, and ≥ 65 years). In the FH I and II trials, patients received 75 mg subcutaneously every 2 weeks (Q2W), with dose increase to 150 mg Q2W at week 12 if week 8 low-density lipoprotein cholesterol (LDL-C) was ≥ 70 mg/dl. In HIGH FH and LONG TERM, patients received 150 mg alirocumab Q2W. RESULTS: Baseline characteristics were similar between treatment groups across all age groups; the proportion of males decreased whereas the proportion of patients with coronary heart disease, diabetes, hypertension, and declining renal function increased with increasing age. Mean LDL-C reductions at week 24 were consistent across age groups (50.6-61.0% and 51.1-65.8% vs. placebo for the 75/150 and 150 mg alirocumab dose regimens, respectively; both non-significant interaction P-values). Treatment-emergent adverse events occurred in similar frequency in alirocumab- and placebo-treated patients regardless of age, except for injection-site reactions, which were more common in alirocumab than placebo but declined in frequency with age. CONCLUSIONS: Alirocumab treatment resulted in significant LDL-C reductions at weeks 12 and 24 and was generally well tolerated in patients with HeFH across all age groups studied.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/sangue , Heterozigoto , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Inibidores de PCSK9 , Adolescente , Adulto , Fatores Etários , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Anticolesterolemiantes/efeitos adversos , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/etiologia , Ensaios Clínicos Fase III como Assunto , Regulação para Baixo , Feminino , Predisposição Genética para Doença , Humanos , Hiperlipoproteinemia Tipo II/complicações , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Pró-Proteína Convertase 9/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
AIMS: Individuals with both diabetes mellitus (DM) and atherosclerotic cardiovascular disease (ASCVD) are at very high risk of cardiovascular events. This post-hoc analysis evaluated efficacy and safety of the PCSK9 inhibitor alirocumab among 984 individuals with DM and ASCVD pooled from 9 ODYSSEY Phase 3 trials. MATERIALS AND METHODS: Changes in low-density lipoprotein cholesterol (LDL-C) and other lipids from baseline to Week 24 were analysed (intention-to-treat) in four pools by alirocumab dosage (150 mg every 2 weeks [150] or 75 mg with possible increase to 150 mg every 2 weeks [75/150]), control (placebo/ezetimibe) and background statin usage (yes/no). RESULTS: At Week 24, LDL-C changes from baseline in pools with background statins were -61.5% with alirocumab 150 (vs -1.0% with placebo), -46.4% with alirocumab 75/150 (vs +6.3% with placebo) and -48.7% with alirocumab 75/150 (vs -20.6% with ezetimibe), and -54.9% with alirocumab 75/150 (vs +4.0% with ezetimibe) without background statins. A greater proportion of alirocumab recipients achieved LDL-C < 70 and < 55 mg/dL at Week 24 vs controls. Alirocumab also resulted in significant reductions in non-high-density lipoprotein cholesterol, apolipoprotein B and lipoprotein(a) vs controls. Alirocumab did not appear to affect glycaemia over 78-104 weeks. Overall safety was similar between treatment groups, with a higher injection-site reaction frequency (mostly mild) with alirocumab. CONCLUSION: Alirocumab significantly reduced LDL-C and other atherogenic lipid parameters, and was generally well tolerated in individuals with DM and ASCVD.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Aterosclerose/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , Ensaios Clínicos Fase III como Assunto/estatística & dados numéricos , Diabetes Mellitus/tratamento farmacológico , Angiopatias Diabéticas/tratamento farmacológico , Ezetimiba/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados , Aterosclerose/complicações , Aterosclerose/epidemiologia , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Patients with previous atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) are at high risk of future cardiovascular events. Despite maximally tolerated doses of statins, many patients still have elevated low-density lipoprotein cholesterol (LDL-C) levels. We evaluated the efficacy and safety of alirocumab in patients with ASCVD and/or HeFH on a maximally tolerated dose of statin (rosuvastatin 20 or 40 mg, atorvastatin 40 or 80 mg, or simvastatin 80 mg, or lower doses with an investigator-approved reason) ± other lipid-lowering therapies from 5 placebo-controlled phase 3 trials (52 to 78 weeks). Patients with (n = 2,449) and without (n = 1,050) ASCVD were pooled from the FH I, FH II, HIGH FH, LONG TERM, and COMBO I trials. Patients with HeFH with (n = 575) and without ASCVD (n = 682) were pooled from all trials except COMBO I. High-intensity statins were utilized in 55.7% to 59.0% and in 72.4% to 87.6% of the ASCVD and the HeFH groups, respectively. Efficacy end points included LDL-C percent change from baseline to week 24 stratified by alirocumab dose. Mean baseline demographics and lipid levels were comparable in alirocumab- and placebo-treated patients. LDL-C reductions from baseline at week 24 ranged from 46.6% to 51.3% for alirocumab 75/150 mg and from 54.1% to 61.9% for alirocumab 150 mg in ASCVD and HeFH groups and were sustained for up to 78 weeks. LDL-C reductions with alirocumab were independent of ASCVD and/or HeFH status (interaction p value >0.05). Concordant results were observed for other lipids analyzed. The overall safety in the subgroups analyzed was similar in both treatment arms. Injection-site reactions were observed more frequently with alirocumab versus placebo.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Aterosclerose/tratamento farmacológico , LDL-Colesterol/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Aterosclerose/sangue , Aterosclerose/complicações , Atorvastatina/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Doença das Coronárias/sangue , Doença das Coronárias/complicações , Doença das Coronárias/tratamento farmacológico , Quimioterapia Combinada , Feminino , Heterozigoto , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/complicações , Hipercolesterolemia/tratamento farmacológico , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/complicações , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Inibidores de PCSK9 , Doença Arterial Periférica/sangue , Doença Arterial Periférica/complicações , Doença Arterial Periférica/tratamento farmacológico , Risco , Rosuvastatina Cálcica/uso terapêutico , Sinvastatina/uso terapêutico , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico , Resultado do TratamentoRESUMO
Circulatory arrest (CA) remains a major unresolved public health problem in the United States; the annual incidence of which is ~0.50 to 0.55 per 1000 population. Despite seminal advances in therapeutic approaches over the past several decades, brain injury continues to be the leading cause of morbidity and mortality after CA. In brief, CA typically results in global cerebral ischemia leading to delayed neuronal death in the hippocampal pyramidal cells as well as in the cortical layers. The dynamic changes occurring in neurons after CA are still unclear, and predicting these neurological changes in the brain still remains a difficult issue. It is hypothesized that the "no-flow" period produces a cytotoxic cascade of membrane depolarization, Ca2+ ion influx, glutamate release, acidosis, and resultant activation of lipases, nucleases, and proteases. Furthermore, during reperfusion injury, neuronal death occurs due to the generation of free radicals by interfering with the mitochondrial respiratory chain. The efficacy of many pharmacological agents for CA patients has often been disappointing, reflecting our incomplete understanding of this enigmatic disease. The primary obstacles to the development of a neuroprotective therapy in CA include uncertainties with regard to the precise cause(s) of neuronal dysfunction and what to target. In this review, we summarize our knowledge of the pathophysiology as well as specific cellular changes in brain after CA and revisit the most important neurofunctional, neuroimaging techniques, and serum biomarkers as potent predictors of neurologic outcome in CA patients.
Assuntos
Isquemia Encefálica , Sinalização do Cálcio , Circulação Cerebrovascular , Hipocampo , Potenciais da Membrana , Células Piramidais , Animais , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Isquemia Encefálica/terapia , Hipocampo/química , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia , Humanos , Células Piramidais/metabolismo , Traumatismo por Reperfusão/diagnóstico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Traumatismo por Reperfusão/terapiaRESUMO
RATIONALE: Cardiac progenitor cells (CPCs) improve left ventricular remodeling and function after acute or chronic myocardial infarction. However, the long-term (>5 weeks) effects, potential tumorigenicity, and fate of transplanted CPCs are unknown. OBJECTIVE: To assess the outcome of CPC therapy at 1 year. METHODS AND RESULTS: Female rats underwent a 90-minute coronary occlusion; 4 hours after reperfusion, they received intracoronarily vehicle or 1 million male, syngeneic CPCs. One year later, CPC-treated rats exhibited smaller scars and more viable myocardium in the risk region, along with improved left ventricular remodeling and regional and global left ventricular function. No tumors were observed. Some transplanted (Y-chromosome(POS)) CPCs (or their progeny) persisted and continued to proliferate, but they failed to acquire a mature cardiomyocyte phenotype and were too few (4-8% of nuclei) to account for the benefits of CPC therapy. Surprisingly, CPC transplantation triggered a prolonged proliferative response of endogenous cells, resulting in increased formation of endothelial cells and Y-chromosome(NEG) CPCs for 12 months and increased formation, for at least 7 months, of small cells that expressed cardiomyocytic proteins (α-sarcomeric actin) but did not have a mature cardiomyocyte phenotype. CONCLUSIONS: The beneficial effects of CPCs on left ventricular remodeling and dysfunction are sustained for at least 1 year and thus are likely to be permanent. Because transplanted CPCs do not differentiate into mature myocytes, their major mechanism of action must involve paracrine actions. These paracrine mechanisms could be very prolonged because some CPCs engraft, proliferate, and persist at 1 year. This is the first report that transplantation of any cell type in the heart induces a proliferative response that lasts at least 1 year. The results strongly support the safety and clinical utility of CPC therapy.
Assuntos
Células-Tronco Adultas/transplante , Infarto do Miocárdio/terapia , Células-Tronco Adultas/química , Células-Tronco Adultas/citologia , Animais , Contagem de Células , Diferenciação Celular , Divisão Celular , Linhagem da Célula , Replicação do DNA , Feminino , Hemodinâmica , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/patologia , Hibridização in Situ Fluorescente , Antígenos Comuns de Leucócito/análise , Masculino , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/fisiopatologia , Miócitos Cardíacos/patologia , Proteínas Proto-Oncogênicas c-kit/análise , Ratos , Ratos Endogâmicos F344 , Método Simples-Cego , Fatores de Tempo , Ultrassonografia , Disfunção Ventricular Esquerda/etiologiaRESUMO
BACKGROUND: Although c-kit(pos) cardiac stem cells (CSCs) preserve left ventricular (LV) function and structure after myocardial infarction, CSC doses have been chosen arbitrarily, and the dose-effect relationship is unknown. METHODS AND RESULTS: Rats underwent a 90-minute coronary occlusion followed by 35 days of reperfusion. Vehicle or CSCs at 5 escalating doses (0.3×10(6), 0.75×10(6), 1.5×10(6), 3.0×10(6), and 6.0×10(6) cells/heart) were given intracoronarily 4 h after reperfusion. The lowest dose (0.3×10(6)) had no effect on LV function and morphology, whereas 0.75, 1.5, and 3.0×10(6) significantly improved regional and global LV function (echocardiography and hemodynamic studies). These 3 doses had similar effects on echocardiographic parameters (infarct wall thickening fraction, LV end-systolic and end-diastolic volumes, LV ejection fraction) and hemodynamic variables (LV end-diastolic pressure, LV dP/dtmax, preload adjusted maximal power, end-systolic elastance, preload recruitable stroke work) and produced similar reductions in apoptosis, scar size, infarct wall thinning, and LV expansion index and similar increases in viable myocardium in the risk region (morphometry). Infusion of 6.0×10(6) CSCs markedly increased postprocedural mortality. Green fluorescent protein and 5-bromo-2'-deoxyuridine staining indicated that persistence of donor cells and formation of new myocytes were negligible with all doses. CONCLUSIONS: Surprisingly, in this rat model of acute myocardial infarction, the dose-response relationship for intracoronary CSCs is flat. A minimal dose between 0.3 and 0.75×10(6) is necessary for efficacy; above this threshold, a 4-fold increase in cell number does not produce greater improvement in LV function or structure. Further increases in cell dose are harmful.
Assuntos
Infarto do Miocárdio/cirurgia , Miocárdio/patologia , Miócitos Cardíacos/transplante , Regeneração , Transplante de Células-Tronco , Função Ventricular Esquerda , Animais , Apoptose , Biomarcadores/metabolismo , Capilares/fisiopatologia , Débito Cardíaco , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Masculino , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Neovascularização Fisiológica , Proteínas Proto-Oncogênicas c-kit/metabolismo , Ratos Endogâmicos F344 , Recuperação de Função Fisiológica , Transplante de Células-Tronco/efeitos adversos , Células-Tronco/metabolismo , Fatores de Tempo , Sobrevivência de Tecidos , Ultrassonografia , Pressão VentricularRESUMO
Despite significant therapeutic advances, the prognosis of patients with heart failure (HF) remains poor, and current therapeutic approaches are palliative in the sense that they do not address the underlying problem of the loss of cardiac tissue. Stem cell-based therapies have the potential to fundamentally transform the treatment of HF by achieving what would have been unthinkable only a few years ago-myocardial regeneration. For the first time since cardiac transplantation, a therapy is being developed to eliminate the underlying cause of HF, not just to achieve damage control. Since the initial report of cell therapy (skeletal myoblasts) in HF in 1998, research has proceeded at lightning speed, and numerous preclinical and clinical studies have been performed that support the ability of various stem cell populations to improve cardiac function and reduce infarct size in both ischemic and nonischemic cardiomyopathy. Nevertheless, we are still at the dawn of this therapeutic revolution. Many important issues (eg, mechanism(s) of action of stem cells, long-term engraftment, optimal cell type(s), and dose, route, and frequency of cell administration) remain to be resolved, and no cell therapy has been conclusively shown to be effective. The purpose of this article is to critically review the large body of work performed with respect to the use of stem/progenitor cells in HF, both at the experimental and clinical levels, and to discuss current controversies, unresolved issues, challenges, and future directions. The review focuses specifically on chronic HF; other settings (eg, acute myocardial infarction, refractory angina) are not discussed.
Assuntos
Insuficiência Cardíaca/terapia , Transplante de Células-Tronco/métodos , Animais , Ensaios Clínicos como Assunto , Humanos , Transplante de Células-Tronco/tendências , Células-Tronco/classificaçãoRESUMO
BACKGROUND: Relevant preclinical models are necessary for further mechanistic and translational studies of c-kit+ cardiac stem cells (CSCs). The present study was undertaken to determine whether intracoronary CSCs are beneficial in a porcine model of chronic ischemic cardiomyopathy. METHODS AND RESULTS: Pigs underwent a 90-minute coronary occlusion followed by reperfusion. Three months later, autologous CSCs (n=11) or vehicle (n=10) were infused into the infarct-related artery. At this time, all indices of left ventricular (LV) function were similar in control and CSC-treated pigs, indicating that the damage inflicted by the infarct in the 2 groups was similar; 1 month later, however, CSC-treated pigs exhibited significantly greater LV ejection fraction (echocardiography) (51.7±2.0% versus 42.9±2.3%, P<0.01), systolic thickening fraction in the infarcted LV wall, and maximum LV dP/dt, as well as lower LV end-diastolic pressure. Confocal microscopy showed clusters of small α-sarcomeric actin-positive cells expressing Ki67 in the scar of treated pigs, consistent with cardiac regeneration. The origin of these cycling myocytes from the injected cells was confirmed in 4 pigs that received enhanced green fluorescent protein -labeled CSCs, which were positive for the cardiac markers troponin I, troponin T, myosin heavy chain, and connexin-43. Some engrafted CSCs also formed vascular structures and expressed α-smooth muscle actin. CONCLUSIONS: Intracoronary infusion of autologous CSCs improves regional and global LV function and promotes cardiac and vascular regeneration in pigs with old myocardial infarction (scar). The results mimic those recently reported in humans (Stem Cell Infusion in Patients with Ischemic CardiOmyopathy [SCIPIO] trial) and establish this porcine model of ischemic cardiomyopathy as a useful and clinically relevant model for studying CSCs.
Assuntos
Cardiomiopatias/cirurgia , Vasos Coronários/fisiologia , Modelos Animais de Doenças , Isquemia Miocárdica/cirurgia , Miócitos Cardíacos/transplante , Transplante de Células-Tronco/métodos , Animais , Cardiomiopatias/patologia , Células Cultivadas , Infusões Intra-Arteriais , Masculino , Isquemia Miocárdica/patologia , Miócitos Cardíacos/fisiologia , Suínos , Transplante AutólogoRESUMO
Although the late phase of ischemic preconditioning is known to be mediated by increased inducible nitric oxide synthase (iNOS) activity, controversy persists regarding the role of iNOS in ischemia/reperfusion (I/R) injury and, specifically, whether this protein is protective or detrimental. We hypothesized that iNOS is protective in myocytes but detrimental in inflammatory cells. To test this hypothesis, we created chimeric mice with iNOS-deficient peripheral blood cells by transplanting iNOS knockout (KO) bone marrow in wild-type (WT) mice after lethal irradiation. 2 months later, the mice underwent a 30-min coronary occlusion followed by 24 h of reperfusion. In WT naïve mice (iNOS(+/+) naïve; group I, n = 17), infarct size was 56.9 ± 2.8% of the risk region. In iNOS KO naïve mice with whole-body iNOS deletion (iNOS(-/-) naïve; group II, n = 10), infarct size was comparable to group I (53.4 ± 3.5%). When irradiated WT mice received marrow from WT mice (iNOS(+/+) chimera; group III, n = 10), infarct size was slightly reduced versus group I (44.3 ± 3.2%), indicating that irradiation and/or transplantation slightly decrease I/R injury. However, when WT mice received marrow from iNOS KO mice (iNOS(-/-) chimera; group IV, n = 14), infarct size was profoundly reduced (22.8 ± 2.1%, P < 0.05 vs. group III), indicating that selective deletion of iNOS from peripheral blood cells (with no change in myocardial iNOS content) induces protection against myocardial infarction. Together with our previous work showing the cardioprotective actions of NO donors, iNOS gene therapy, and cardiac-specific overexpression of iNOS, these data support a complex, dual role of iNOS in myocardial infarction (i.e., protective in myocytes but deleterious in blood cells). To our knowledge, this is the first study to identify a critical role of iNOS in peripheral blood cells as a mediator of myocardial I/R injury. The results support heretofore unknown differential actions of iNOS depending on cell source and have important translational implications.
Assuntos
Células Sanguíneas/enzimologia , Infarto do Miocárdio/enzimologia , Traumatismo por Reperfusão Miocárdica/enzimologia , Óxido Nítrico Sintase Tipo II/metabolismo , Animais , Células da Medula Óssea/enzimologia , Células-Tronco Hematopoéticas/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infarto do Miocárdio/etiologia , Traumatismo por Reperfusão Miocárdica/complicações , Quimeras de TransplanteRESUMO
A growing body of evidence indicates that carbon monoxide (CO), once perceived merely as a poisonous gas, exerts antiapoptotic and cytoprotective effects. Using a water-soluble CO-releasing molecule (CORM) tricarbonylchloro(glycinato)ruthenium(II) (CORM-3), we previously reported that CO induces a delayed protection against myocardial infarction similar to that observed in the late phase of ischemic preconditioning (PC). In the current study, we investigated the molecular mechanisms underlying this cardioprotective effect. The impact on apoptotic signaling pathways was first examined in the setting of ischemia/reperfusion injury. Mice were pretreated with CORM-3 or iCORM-3 (which does not release CO) and subjected to coronary occlusion/reperfusion 24h later. In mice that received CORM-3, there was a significant reduction in markers of apoptosis (cleaved lamin A, cleaved caspase-3, and cleaved PARP-1) after ischemia/reperfusion injury. To elucidate the mechanism of CORM-3-induced cardioprotection we further examined the activation of transcription factors and induction of cardioprotective and apoptosis modulating proteins. Infusion of CORM-3 rapidly activated the stress-responsive transcription factors nuclear factor kappaB (NF-κB), signal transducers and activators of transcription (STAT)1, STAT3, and NF-E2-related factor-2 (Nrf2). This was followed 24h later by upregulation of cardioprotective proteins (heme oxygenase-1 [HO-1], cyclooxygenase-2 [COX-2], and extracellular superoxide dismutase [Ec-SOD]) and antiapoptotic proteins involving both the mitochondria-mediated (Mcl-1) and the death receptor-mediated (c-FLIP(S) and c-FLIP(L)) apoptosis pathways. We conclude that CO released by CORM-3 triggers a cardioprotective signaling cascade that recruits the transcription factors NF-κB, STAT1/3, and Nrf2 with a subsequent increase in cardioprotective and antiapoptotic molecules in the myocardium leading to the late PC-mimetic infarct-sparing effects. This article is part of a Special Issue entitled 'Possible Editorial'.
Assuntos
Apoptose/efeitos dos fármacos , Monóxido de Carbono/metabolismo , Precondicionamento Isquêmico Miocárdico , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/metabolismo , Compostos Organometálicos/farmacologia , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Ciclo-Oxigenase 2/metabolismo , Heme Oxigenase-1/metabolismo , Masculino , Camundongos , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Fisiológico , Superóxido Dismutase/metabolismoRESUMO
Although statins impart a number of cardiovascular benefits, whether statin therapy during the peri-infarct period improves subsequent myocardial structure and function remains unclear. Thus, we evaluated the effects of atorvastatin on cardiac function, remodeling, fibrosis, and apoptosis after myocardial infarction (MI). Two groups of rats were subjected to permanent coronary occlusion. Group II (nâ=â14) received oral atorvastatin (10 mg/kg/d) daily for 3 wk before and 4 wk after MI, while group I (nâ=â12) received equivalent doses of vehicle. Infarct size (Masson's trichrome-stained sections) was similar in both groups. Compared with group I, echocardiographic left ventricular ejection fraction (LVEF) and fractional area change (FAC) were higher while LV end-diastolic volume (LVEDV) and LV end-systolic and end-diastolic diameters (LVESD and LVEDD) were lower in treated rats. Hemodynamically, atorvastatin-treated rats exhibited significantly higher dP/dt(max), end-systolic elastance (Ees), and preload recruitable stroke work (PRSW) and lower LV end-diastolic pressure (LVEDP). Morphometrically, infarct wall thickness was greater in treated rats. The improvement of LV function by atorvastatin was associated with a decrease in hydroxyproline content and in the number of apoptotic cardiomyocyte nuclei. We conclude that atorvastatin therapy during the peri-infarct period significantly improves LV function and limits adverse LV remodeling following MI independent of a reduction in infarct size. These salubrious effects may be due in part to a decrease in myocardial fibrosis and apoptosis.
Assuntos
Ácidos Heptanoicos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Infarto do Miocárdio/fisiopatologia , Pirróis/farmacologia , Disfunção Ventricular Esquerda/tratamento farmacológico , Remodelação Ventricular/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Atorvastatina , Feminino , Ácidos Heptanoicos/administração & dosagem , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hidroxiprolina/metabolismo , Contração Muscular/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Pirróis/administração & dosagem , Pirróis/uso terapêutico , Ratos , Ratos Endogâmicos F344RESUMO
Hematopoietic cytokines, traditionally known to influence cellular proliferation, differentiation, maturation, and lineage commitment in the bone marrow, include granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor, stem cell factor, Flt-3 ligand, and erythropoietin among others. Emerging evidence suggests that these cytokines also exert multifarious biological effects on diverse nonhematopoietic organs and tissues. Although the precise mechanisms remain unclear, numerous studies in animal models of myocardial infarction (MI) and heart failure indicate that hematopoietic cytokines confer potent cardiovascular benefits, possibly through mobilization and subsequent homing of bone marrow-derived cells into the infarcted heart with consequent induction of myocardial repair involving multifarious mechanisms. In addition, these cytokines are also known to exert direct cytoprotective effects. However, results from small-scale clinical trials of G-CSF therapy as a single agent after acute MI have been discordant and largely disappointing. It is likely that cardiac repair following cytokine therapy depends on a number of known and unknown variables, and further experimental and clinical studies are certainly warranted to accurately determine the true therapeutic potential of such therapy. In this review, we discuss the biological features of several key hematopoietic cytokines and present the basic and clinical evidence pertaining to cardiac repair with hematopoietic cytokine therapy.
Assuntos
Células da Medula Óssea/fisiologia , Citocinas/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/fisiopatologia , Animais , Células da Medula Óssea/citologia , Movimento Celular/efeitos dos fármacos , Citocinas/farmacologia , Eritropoetina/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Humanos , Proteínas de Membrana/uso terapêutico , Modelos AnimaisRESUMO
Pharmacological studies have shown that signal transducers and activators of transcription (STATs) are necessary for the delayed cardioprotection of ischemic preconditioning (PC). However, pharmacologic STAT inhibitors are not specific; furthermore, the individual role of STAT3 in late PC remains unknown. The objectives of the study were (i) to create an inducible, cardiac-specific STAT3 knockout mouse; (ii) to verify whether STAT3 deletion has any adverse effects in the short term (~1 month); and (iii) to use this novel tool to evaluate the role of STAT3 in the PC-induced upregulation of cardioprotective and anti-apoptotic proteins. We created an inducible, cardiomyocyte-restricted STAT3 deficient mouse (MCM TG:STAT3(flox/flox)) by interbreeding STAT3(flox/flox) mice and tamoxifen-inducible MCM TG mice. Treatment of MCM TG:STAT3(flox/flox) mice with tamoxifen resulted in deletion of STAT3 specifically in cardiac myocytes, concomitant with abrogation of ischemic PC-induced Tyr-705 and Ser-727 phosphorylation of STAT3 and increased STAT3 DNA-binding activity. In vehicle-treated MCM TG:STAT3(flox/flox) mice, ischemic PC increased the expression of cardioprotective (COX-2 and HO-1) and anti-apoptotic (e.g., Mcl-1, Bcl-x(L), c-FLIP(L), c-FLIP(S)) proteins 24h later; in contrast, in tamoxifen-treated MCM TG:STAT3(flox/flox) mice this increase was completely absent. Deletion of STAT3 had no apparent adverse effects on LV structure or function after 35 days. We have developed a novel inducible, cardiomyocyte-restricted STAT3 deficient mouse that can be used to specifically interrogate the role of this transcription factor in cardiovascular pathophysiology in vivo. Our data demonstrate, for the first time, that recruitment of STAT3 plays an obligatory role in the upregulation of cardioprotective and anti-apoptotic proteins and suggest that STAT3 activation is important in inhibiting both the death receptor pathway (which is modulated by c-FLIP(L) and c-FLIP(S)) and the mitochondrial pathway (which is mediated by Mcl-1 and Bcl-x(L)).
Assuntos
Precondicionamento Isquêmico , Fator de Transcrição STAT3/metabolismo , Animais , Apoptose/genética , Apoptose/fisiologia , Western Blotting , Células Cultivadas , Ensaio de Desvio de Mobilidade Eletroforética , Masculino , Camundongos , Camundongos Mutantes , Miócitos Cardíacos/metabolismo , Fosforilação , Fator de Transcrição STAT3/genética , Proteína X Associada a bcl-2/metabolismo , Proteína de Morte Celular Associada a bcl/metabolismoRESUMO
Although ß-adrenoceptor (ß-AR) blockade is an important mode of therapy for congestive heart failure (CHF), subcellular mechanisms associated with its beneficial effects are not clear. Three weeks after inducing myocardial infarction (MI), rats were treated daily with or without 20 and 75 mg/kg atenolol, a selective ß(1) -AR antagonist, or propranolol, a non-selective ß-AR antagonist, for 5 weeks. Sham operated rats served as controls. All animals were assessed haemodynamically and echocardiographically and the left ventricle (LV) was processed for the determination of myofibrillar ATPase activity, α- and ß-myosin heavy chain (MHC) isoforms and gene expression as well as cardiac troponin I (cTnI) phosphorylation. Both atenolol and propranolol at 20 and 75 mg/kg doses attenuated cardiac hypertrophy and lung congestion in addition to increasing LV ejection fraction and LV systolic pressure as well as decreasing heart rate, LV end-diastolic pressure and LV diameters in the infarcted animals. Treatment of infarcted animals with these agents also attenuated the MI-induced depression in myofibrillar Ca(2+) -stimulated ATPase activity and phosphorylated cTnI protein content. The MI-induced decrease in α-MHC and increase in ß-MHC protein content were attenuated by both atenolol and propranolol at low and high doses; however, only high dose of propranolol was effective in mitigating changes in the gene expression for α-MHC and ß-MHC. Our results suggest that improvement of cardiac function by ß-AR blockade in CHF may be associated with attenuation of myofibrillar remodelling.
Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Insuficiência Cardíaca/prevenção & controle , Coração/efeitos dos fármacos , Miocárdio/metabolismo , Animais , Atenolol/farmacologia , Northern Blotting , ATPase de Ca(2+) e Mg(2+)/metabolismo , Relação Dose-Resposta a Droga , Ecocardiografia , Expressão Gênica/efeitos dos fármacos , Coração/fisiopatologia , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Masculino , Infarto do Miocárdio/complicações , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/prevenção & controle , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Fosforilação/efeitos dos fármacos , Propranolol/farmacologia , Ratos , Ratos Sprague-Dawley , Troponina I/metabolismo , Remodelação Ventricular/efeitos dos fármacosRESUMO
Adult bone marrow-derived very small embryonic-like stem cells (VSEL-SCs) exhibit a Sca-1(+)/Lin(-)/CD45(-) phenotype and can differentiate into various cell types, including cardiomyocytes and endothelial cells. We have previously reported that transplantation of a small number (1 × 10(6)) of freshly isolated, non-expanded VSEL-SCs into infarcted mouse hearts resulted in improved left ventricular (LV) function and anatomy. Clinical translation, however, will require large numbers of cells. Because the frequency of VSEL-SCs in the marrow is very low, we examined whether VSEL-SCs can be expanded in culture without loss of therapeutic efficacy. Mice underwent a 30 min. coronary occlusion followed by reperfusion and, 48 hrs later, received an intramyocardial injection of vehicle (group I, n = 11), 1 × 10(5) enhanced green fluorescent protein (EGFP)-labelled expanded untreated VSEL-SCs (group II, n = 7), or 1 × 10(5) EGFP-labelled expanded VSEL-SCs pre-incubated in a cardiogenic medium (group III, n = 8). At 35 days after myocardial infarction (MI), mice treated with pre-incubated VSEL-SCs exhibited better global and regional LV systolic function and less LV hypertrophy compared with vehicle-treated controls. In contrast, transplantation of expanded but untreated VSEL-SCs did not produce appreciable reparative benefits. Scattered EGFP(+) cells expressing α-sarcomeric actin, platelet endothelial cell adhesion molecule (PECAM)-1, or von Willebrand factor were present in VSEL-SC-treated mice, but their numbers were very small. No tumour formation was observed. We conclude that VSEL-SCs expanded in culture retain the ability to alleviate LV dysfunction and remodelling after a reperfused MI provided that they are exposed to a combination of cardiomyogenic growth factors and cytokines prior to transplantation. Counter intuitively, the mechanism whereby such pre-incubation confers therapeutic efficacy does not involve differentiation into new cardiac cells. These results support the potential therapeutic utility of VSEL-SCs for cardiac repair.
Assuntos
Proliferação de Células/efeitos dos fármacos , Células-Tronco Embrionárias , Injeções Intramusculares/métodos , Infarto do Miocárdio/terapia , Miocárdio/patologia , Transplante de Células-Tronco/métodos , Função Ventricular Esquerda , Animais , Medula Óssea/fisiologia , Técnicas de Cultura de Células , Oclusão Coronária/complicações , Meios de Cultura , Citocinas/farmacologia , Modelos Animais de Doenças , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/transplante , Proteínas de Fluorescência Verde/análise , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Remodelação VentricularRESUMO
BACKGROUND: Administration of cardiac progenitor cells (CPCs) 4 hours after reperfusion ameliorates left ventricular function in rats with acute myocardial infarction (MI). Clinically, however, this approach is not feasible, because expansion of autologous CPCs after acute MI requires several weeks. Therefore, we sought to determine whether CPCs are beneficial in the more clinically relevant setting of an old MI (scar). METHODS AND RESULTS: One month after coronary occlusion/reperfusion, rats received an intracoronary infusion of vehicle or enhanced green fluorescent protein-labeled CPCs. Thirty-five days later, CPC-treated rats exhibited more viable myocardium in the risk region, less fibrosis in the noninfarcted region, and improved left ventricular function. Cells that stained positive for enhanced green fluorescent protein that expressed cardiomyocyte, endothelial, and vascular smooth muscle cell markers were observed only in 7 of 17 treated rats and occupied only 2.6% and 1.1% of the risk and noninfarcted regions, respectively. Transplantation of CPCs was associated with increased proliferation and expression of cardiac proteins by endogenous CPCs. CONCLUSIONS: Intracoronary administration of CPCs in the setting of an old MI produces beneficial structural and functional effects. Although exogenous CPCs can differentiate into new cardiac cells, this mechanism is not sufficient to explain the benefits, which suggests paracrine effects; among these, the present data identify activation of endogenous CPCs. This is the first report that CPCs are beneficial in the setting of an old MI when given by intracoronary infusion, the most widely applicable therapeutic approach in patients. Furthermore, this is the first evidence that exogenous CPC administration activates endogenous CPCs. These results open the door to new therapeutic applications for the use of autologous CPCs in patients with old MI and chronic ischemic cardiomyopathy.
Assuntos
Infarto do Miocárdio/terapia , Transplante de Células-Tronco/métodos , Disfunção Ventricular Esquerda/terapia , Animais , Proliferação de Células , Vasos Coronários , Fibrose , Proteínas de Fluorescência Verde , Infarto do Miocárdio/fisiopatologia , Miocárdio/citologia , Comunicação Parácrina , Ratos , Ratos Endogâmicos F344 , Traumatismo por Reperfusão/terapia , Fatores de TempoRESUMO
This study investigated whether improvement in cardiac function and attenuation of cardiac remodeling by some beta-adrenoceptor (beta-AR) antagonists were associated with a depression in sympathetic activity in congestive heart failure (CHF) due to myocardial infarction (MI). Although cardiac dysfunction, hypertrophy and dilatation as well as increased plasma level of catecholamines are known to occur in CHF, the relationship between these parameters is poorly understood. Three weeks after occlusion of the coronary artery, rats were treated daily with 20 and 75 mg/kg of either atenolol or propranolol for 5 weeks. Sham-operated rats served as controls. Both atenolol and propranolol at 20 and 75 mg/kg doses attenuated the MI-induced cardiac hypertrophy, increases in left ventricular (LV) end-diastolic pressure, LV end-systolic volume and LV end-diastolic volume as well as depressions in LV systolic pressure, LV fractional shortening and cardiac output. PR interval was decreased and QT( c ) interval was increased in CHF; these alterations were ameliorated by both atenolol and propranolol. The increased level of plasma epinephrine in CHF was also depressed by both low and high doses of atenolol and propranolol whereas the increased level of plasma norepinephrine was reduced by high but not low doses of these drugs. The results indicate that the beneficial effects of beta-AR antagonists on cardiac remodeling and heart dysfunction in CHF may be due to the blockade of beta-ARs in the myocardium and a depression in the sympathetic activity.
Assuntos
Antagonistas Adrenérgicos beta/toxicidade , Antagonistas Adrenérgicos beta/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Sistema Nervoso Simpático/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Atenolol/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Depressão Química , Eletrocardiografia/efeitos dos fármacos , Epinefrina/sangue , Insuficiência Cardíaca/diagnóstico por imagem , Frequência Cardíaca/efeitos dos fármacos , Masculino , Norepinefrina/sangue , Tamanho do Órgão/efeitos dos fármacos , Propranolol/farmacologia , Ratos , Ratos Sprague-Dawley , UltrassonografiaRESUMO
BACKGROUND: Although inducible nitric oxide synthase (iNOS) is known to impart powerful protection against myocardial infarction, the mechanism for this salubrious action remains unclear. METHODS AND RESULTS: Adenovirus-mediated iNOS gene transfer in mice resulted 48 to 72 hours later in increased expression not only of iNOS protein but also of heme oxygenase (HO)-1 mRNA and protein; HO-2 protein expression did not change. iNOS gene transfer markedly reduced infarct size in wild-type mice, but this effect was completely abrogated in HO-1(-/-) mice. At 48 hours after iNOS gene transfer, nuclear factor-kappaB was markedly activated. In transgenic mice with cardiomyocyte-restricted expression of a dominant negative mutant of IkappaBalpha (IkappaBalpha(S32A,S36A)), both basal HO-1 levels and upregulation of HO-1 by iNOS gene transfer were suppressed. Chromatin immunoprecipitation analysis of mouse hearts provided direct evidence that nuclear factor-kappaB subunits p50 and p65 were recruited to the HO-1 gene promoter (-468 to -459 bp) 48 hours after iNOS gene transfer. CONCLUSIONS: This study demonstrates for the first time the existence of a close functional coupling between cardiac iNOS and cardiac HO-1: iNOS upregulates HO-1 by augmenting nuclear factor-kappaB binding to the region of the HO-1 gene promoter from -468 to -459 bp, and HO-1 then mediates the cardioprotective effects of iNOS. These results also reveal an important role of nuclear factor-kappaB in both basal and iNOS-induced expression of cardiac HO-1. Collectively, the present findings significantly expand our understanding of the regulation of cardiac HO-1 and of the mechanism whereby iNOS exerts its cardioprotective actions.
Assuntos
Terapia Genética/métodos , Coração/fisiologia , Heme Oxigenase-1/metabolismo , Infarto do Miocárdio/terapia , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Adenoviridae/genética , Animais , Bilirrubina/metabolismo , Temperatura Corporal , Feminino , Técnicas de Transferência de Genes , Frequência Cardíaca , Heme Oxigenase-1/genética , Proteínas I-kappa B/genética , Masculino , Camundongos , Camundongos Transgênicos , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Inibidor de NF-kappaB alfa , Óxido Nítrico Sintase Tipo II/metabolismo , Regiões Promotoras Genéticas/fisiologia , RNA Mensageiro/metabolismo , Regulação para Cima/fisiologiaRESUMO
We have previously reported that administration of granulocyte colony-stimulating factor (G-CSF)+Flt-3 ligand (FL) or G-CSF+stem cell factor (SCF) improves left ventricular (LV) function and halts LV remodeling at 35 d after myocardial infarction (MI). In the current study, we investigated whether these beneficial effects are sustained in the long term - an issue of fundamental importance for clinical translation. Mice undergoing a 30-min coronary occlusion followed by reperfusion received vehicle (group I), G-CSF+FL (group II), G-CSF+SCF (group III), or G-CSF alone (group IV) starting 4 h after reperfusion and were euthanized 48 wk later. LV structure and function were assessed by serial echocardiography before and at 48 h and 4, 8, 16, 32, and 48 wk after MI. During follow-up, mice in group I exhibited worsening of LV function and progressive LV remodeling. Compared with group I, both groups II and III exhibited improved LV EF at 4 wk after MI; however, only in group II was this improvement sustained at 48 wk. Group II was also the only group in which the decrease in infarct wall thickening fraction, the LV dilatation, and the increase in LV mass were attenuated vs. group I. We conclude that the beneficial effect of G-CSF+FL on postinfarction LV dysfunction and remodeling is sustained for at least 11 months, and thus is likely to be permanent. In contrast, the effect of G-CSF+SCF was not sustained beyond the first few weeks, and G-CSF alone is ineffective. To our knowledge, this is the first long-term study of cytokines in postinfarction LV remodeling. The results reveal heretofore unknown differential actions of cytokines and have important translational implications.