RESUMEN
The benefits of exercise on the heart are well recognized, and clinical studies have demonstrated that exercise is an intervention that can improve cardiac function in heart failure patients. This has led to significant research into understanding the key mechanisms responsible for exercise-induced cardiac protection. Here, we summarize molecular mechanisms that regulate exercise-induced cardiac myocyte growth and proliferation. We discuss in detail the effects of exercise on other cardiac cells, organelles, and systems that have received less or little attention and require further investigation. This includes cardiac excitation and contraction, mitochondrial adaptations, cellular stress responses to promote survival (heat shock response, ubiquitin-proteasome system, autophagy-lysosomal system, endoplasmic reticulum unfolded protein response, DNA damage response), extracellular matrix, inflammatory response, and organ-to-organ crosstalk. We summarize therapeutic strategies targeting known regulators of exercise-induced protection and the challenges translating findings from bench to bedside. We conclude that technological advancements that allow for in-depth profiling of the genome, transcriptome, proteome and metabolome, combined with animal and human studies, provide new opportunities for comprehensively defining the signaling and regulatory aspects of cell/organelle functions that underpin the protective properties of exercise. This is likely to lead to the identification of novel biomarkers and therapeutic targets for heart disease.
Asunto(s)
Fenómenos Fisiológicos Cardiovasculares , Ejercicio Físico/fisiología , Cardiopatías/prevención & control , Corazón/fisiología , Miocitos Cardíacos/fisiología , Animales , Genoma , Humanos , TranscriptomaRESUMEN
Cardiac myocyte membranes contain lipids which remodel dramatically in response to heart growth and remodeling. Lipid species have both structural and functional roles. Physiological and pathological cardiac remodeling have very distinct phenotypes, and the identification of molecular differences represent avenues for therapeutic interventions. Whether the abundance of specific lipid classes is different in physiological and pathological models was largely unknown. The aim of this study was to determine whether distinct lipids are regulated in settings of physiological and pathological remodeling, and if so, whether modulation of differentially regulated lipids could modulate heart size and function. Lipidomic profiling was performed on cardiac-specific transgenic mice with 1) physiological cardiac hypertrophy due to increased Insulin-like Growth Factor 1 (IGF1) receptor or Phosphoinositide 3-Kinase (PI3K) signaling, 2) small hearts due to depressed PI3K signaling (dnPI3K), and 3) failing hearts due to dilated cardiomyopathy (DCM). In hearts of dnPI3K and DCM mice, several phospholipids (plasmalogens) were decreased and sphingolipids increased compared to mice with physiological hypertrophy. To assess whether restoration of plasmalogens could restore heart size or cardiac function, dnPI3K and DCM mice were administered batyl alcohol (BA; precursor to plasmalogen biosynthesis) in the diet for 16weeks. BA supplementation increased a major plasmalogen species (p18:0) in the heart but had no effect on heart size or function. This may be due to the concurrent reduction in other plasmalogen species (p16:0 and p18:1) with BA. Here we show that lipid species are differentially regulated in settings of physiological and pathological remodeling. Restoration of lipid species in the failing heart warrants further examination.
Asunto(s)
Cardiomegalia/metabolismo , Éteres de Glicerilo/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Miocardio/metabolismo , Plasmalógenos/metabolismo , Remodelación Ventricular/efectos de los fármacos , Animales , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/genética , Cardiomegalia/patología , Ratones , Ratones Transgénicos , Miocardio/patología , Plasmalógenos/genética , Remodelación Ventricular/genéticaRESUMEN
BACKGROUND: Atrial fibrillation is common and management by pharmacotherapy is limited by modest efficacy and significant toxicities. Pulmonary vein isolation (PVI) is a safe and effective alternative in select patients with atrial fibrillation. However, prolonged procedure time raises concerns of health risks from radiation exposure. This study aims to determine the significance of radiation exposure from PVI. METHODS: In this study, we retrospectively reviewed patient demographics, fluoroscopy time, entrance skin dose and dose area product in 80 cases of PVI, radiofrequency ablation for atrial flutter and diagnostic coronary angiogram performed in our institution. RESULTS: Compared to other procedures, patients who underwent PVI were younger (age, mean±standard error of mean, 59.4±1.1 years old, p<0.0001) and were more likely to be male (82%, p<0.001). Body mass index was similar between the three groups. The median (and interquartile range) fluoroscopy time was similar between PVI (20.8 and 13.1-30.7mins) and flutter ablation (17.6 and 11.1-26.1mins) but longer than diagnostic angiography (4.2 and 2.3-6.7mins, p<0.0001). Entrance skin dose was similar between PVI and flutter ablation groups but significantly higher in the diagnostic angiography group, with median and IQR for PVI vs. flutter ablation vs. diagnostic angiography, 100.4 (52.8-179.9) vs. 73.2 (37.0-142.1) vs. 393.5 (276.1-555.6) mGy (p<0.0001). Dose area product in PVI (1831.2 and 887.7-3460.8cGycm2) was higher than flutter ablation (1077.8 and 452.9-2410.2cGycm2, p<0.05) but lower than the diagnostic angiography group (3446.8 and 2341.9-5283.1cGycm2, p<0.0001). The fluoroscopy time and entrance skin dose for PVI decreased over time, likely due to increased operator experience. CONCLUSIONS: Despite prolonged procedure time, radiation exposure from PVI was comparable to, or lower than, other fluoroscopy-guided cardiac procedures.
Asunto(s)
Fibrilación Atrial/cirugía , Ablación por Catéter/métodos , Angiografía Coronaria , Fluoroscopía , Sistema de Conducción Cardíaco/cirugía , Venas Pulmonares/cirugía , Cirugía Asistida por Computador/métodos , Anciano , Fibrilación Atrial/diagnóstico , Relación Dosis-Respuesta en la Radiación , Femenino , Sistema de Conducción Cardíaco/fisiopatología , Frecuencia Cardíaca , Humanos , Angiografía por Resonancia Magnética , Masculino , Persona de Mediana Edad , Venas Pulmonares/diagnóstico por imagen , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Expression of the miR-34 family (miR-34a, -34b, -34c) is elevated in settings of heart disease, and inhibition with antimiR-34a/antimiR-34 has emerged as a promising therapeutic strategy. Under chronic cardiac disease settings, targeting the entire miR-34 family is more effective than targeting miR-34a alone. The identification of transcription factor (TF)-miRNA regulatory networks has added complexity to understanding the therapeutic potential of miRNA-based therapies. Here, we sought to determine whether antimiR-34 targets secondary miRNAs via TFs which could contribute to antimiR-34-mediated protection. Using miRNA-Seq we identified differentially regulated miRNAs in hearts from mice with cardiac pathology due to transverse aortic constriction (TAC), and focused on miRNAs which were also regulated by antimiR-34. Two clusters of stress-responsive miRNAs were classified as "pathological" and "cardioprotective," respectively. Using ChIPBase we identified 45 TF binding sites on the promoters of "pathological" and "cardioprotective" miRNAs, and 5 represented direct targets of miR-34, with the capacity to regulate other miRNAs. Knockdown studies in a cardiomyoblast cell line demonstrated that expression of 2 "pathological" miRNAs (let-7e, miR-31) was regulated by one of the identified TFs. Furthermore, by qPCR we confirmed that expression of let-7e and miR-31 was lower in hearts from antimiR-34 treated TAC mice; this may explain why targeting the entire miR-34 family is more effective than targeting miR-34a alone. Finally, we showed that Acsl4 (a common target of miR-34, let-7e and miR-31) was increased in hearts from TAC antimiR-34 treated mice. In summary, antimiR-34 regulates the expression of other miRNAs and this has implications for drug development.
Asunto(s)
Cardiomegalia/terapia , Redes Reguladoras de Genes , Insuficiencia Cardíaca/terapia , MicroARNs/antagonistas & inhibidores , MicroARNs/metabolismo , Adulto , Análisis de Varianza , Animales , Cardiomegalia/metabolismo , Línea Celular , Coenzima A Ligasas/genética , Coenzima A Ligasas/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Insuficiencia Cardíaca/metabolismo , Ventrículos Cardíacos/química , Ventrículos Cardíacos/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos , MicroARNs/análisis , Miocitos Cardíacos/química , Miocitos Cardíacos/metabolismo , Placebos , Análisis de Secuencia de ARN , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Regular physical activity or exercise training can lead to heart enlargement known as cardiac hypertrophy. Cardiac hypertrophy is broadly defined as an increase in heart mass. In adults, cardiac hypertrophy is often considered a poor prognostic sign because it often progresses to heart failure. Heart enlargement in a setting of cardiac disease is referred to as pathological cardiac hypertrophy and is typically characterized by cell death and depressed cardiac function. By contrast, physiological cardiac hypertrophy, as occurs in response to chronic exercise training (i.e. the 'athlete's heart'), is associated with normal or enhanced cardiac function. The following chapter describes the morphologically distinct types of heart growth, and the key role of the insulin-like growth factor 1 (IGF1) - phosphoinositide 3-kinase (PI3K)-Akt signaling pathway in regulating exercise-induced physiological cardiac hypertrophy and cardiac protection. Finally we summarize therapeutic approaches that target the IGF1-PI3K-Akt signaling pathway which are showing promise in preclinical models of heart disease.
Asunto(s)
Cardiomegalia/fisiopatología , Ejercicio Físico/fisiología , Factor I del Crecimiento Similar a la Insulina/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Animales , Cardiomegalia/metabolismo , Humanos , Modelos Cardiovasculares , Condicionamiento Físico Animal/fisiologíaRESUMEN
KEY POINTS: MicroRNA (miRNA)-based therapies are in development for numerous diseases, including heart disease. Currently, very limited basic information is available on the regulation of specific miRNAs in male and female hearts in settings of disease. The identification of sex-specific miRNA signatures has implications for translation into the clinic and suggests the need for customised therapy. In the present study, we found that a miRNA-based treatment inhibiting miRNA-34a (miR-34a) was more effective in females in a setting of moderate dilated cardiomyopathy than in males. Furthermore, the treatment showed little benefit for either sex in a setting of more severe dilated cardiomyopathy associated with atrial fibrillation. The results highlight the importance of understanding the effect of miRNA-based therapies in cardiac disease settings in males and females. ABSTRACT: MicroRNA (miRNA)-34a (miR-34a) is elevated in the diseased heart in mice and humans. Previous studies have shown that inhibiting miR-34a in male mice in settings of pathological cardiac hypertrophy or ischaemia protects the heart against progression to heart failure. Whether inhibition of miR-34a protects the female heart is unknown. Furthermore, the therapeutic potential of silencing miR-34a in settings of dilated cardiomyopathy (DCM) and atrial fibrillation (AF) has not been assessed previously. In the present study, we examined the effect of silencing miR-34a in males and females in (1) a model of moderate DCM and (2) a model of severe DCM with AF. The cardiac disease models were administered with a locked nucleic acid-modified oligonucleotide (LNA-antimiR-34a) at 6-7 weeks of age when the models display cardiac dysfunction and conduction abnormalities. Cardiac function and morphology were measured 6 weeks after treatment. In the present study, we show that inhibition of miR-34a provides more protection in the DCM model in females than males. Disease prevention in LNA-antimiR-34a treated DCM female mice was characterized by attenuated heart enlargement and lung congestion, lower expression of cardiac stress genes (B-type natriuretic peptide, collagen gene expression), less cardiac fibrosis and better cardiac function. There was no evidence of significant protection in the severe DCM and AF model in either sex. Sex- and treatment-dependent regulation of miRNAs was also identified in the diseased heart, and may explain the differential response of males and females. These studies highlight the importance of examining the impact of miRNA-based drugs in both sexes and under different disease conditions.
Asunto(s)
Cardiomegalia/metabolismo , Cardiomiopatía Dilatada/metabolismo , Insuficiencia Cardíaca/metabolismo , Corazón/fisiopatología , MicroARNs/metabolismo , Animales , Cardiomegalia/fisiopatología , Modelos Animales de Enfermedad , Femenino , Insuficiencia Cardíaca/fisiopatología , Masculino , Ratones , Péptidos Natriuréticos/metabolismo , Caracteres Sexuales , Remodelación Ventricular/fisiologíaRESUMEN
Pneumococcal Conjugate Vaccines (PCVs) have substantially reduced the burden of disease caused by Streptococcus pneumoniae (the pneumococcus). However, protection is limited to vaccine serotypes, and when administered to children who are colonized with pneumococci at the time of vaccination, immune responses to the vaccine are blunted. Here, we investigate the potential of a killed whole cell pneumococcal vaccine (WCV) to reduce existing pneumococcal carriage and mucosal disease when given therapeutically to infant mice colonized with pneumococci. We show that a single dose of WCV reduced pneumococcal carriage density in an antibody-dependent manner. Therapeutic vaccination induced robust immune responses to pneumococcal surface antigens CbpA, PspA (family 1) and PiaA. In a co-infection model of otitis media, a single dose of WCV reduced pneumococcal middle ear infection. Lastly, in a two-dose model, therapeutic administration of WCV reduced nasal shedding of pneumococci. Taken together, our data demonstrate that WCV administered in colonized mice reduced pneumococcal density in the nasopharynx and the middle ear, and decreased shedding. WCVs would be beneficial in low and middle-income settings where pneumococcal carriage in children is high.
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Otitis Media , Infecciones Neumocócicas , Lactante , Niño , Humanos , Animales , Ratones , Streptococcus pneumoniae , Infecciones Neumocócicas/prevención & control , Otitis Media/prevención & control , Vacunas Neumococicas , Vacunación , Serogrupo , Vacunas Conjugadas , Nasofaringe , Portador Sano/prevención & controlRESUMEN
Heat shock proteins are a family of proteins that are produced by cells in response to exposure to stressful conditions. The best studied heat shock protein is HSP70, which is known to act as a molecular chaperone to maintain cellular homeostasis and inhibit protein aggregation in response to stress. While early animal studies suggested that increasing HSP70 in the heart (using a transgenic, gene transfer or pharmacological approach) provided cardiac protection against acute cardiac stress, recent studies have found no benefit of increasing HSP70 in mouse models of chronic cardiac stress. As HSP70 has been considered a potential therapeutic target, it is important to comprehensively assess HSP70 therapies in preclinical models of acute and chronic cardiac disease.
Asunto(s)
Proteínas HSP70 de Choque Térmico/antagonistas & inhibidores , Cardiopatías/tratamiento farmacológico , Cardiopatías/metabolismo , Enfermedad Aguda , Animales , Enfermedad Crónica , Proteínas HSP70 de Choque Térmico/metabolismo , Humanos , RatonesRESUMEN
Expression of miR-154 is upregulated in the diseased heart and was previously shown to be upregulated in the lungs of patients with pulmonary fibrosis. However, the role of miR-154 in a model of sustained pressure overload-induced cardiac hypertrophy and fibrosis had not been assessed. To examine the role of miR-154 in the diseased heart, adult male mice were subjected to transverse aortic constriction for four weeks, and echocardiography was performed to confirm left ventricular hypertrophy and cardiac dysfunction. Mice were then subcutaneously administered a locked nucleic acid antimiR-154 or control over three consecutive days (25 mg/kg/day) and cardiac function was assessed 8 weeks later. Here, we demonstrate that therapeutic inhibition of miR-154 in mice with pathological hypertrophy was able to protect against cardiac dysfunction and attenuate adverse cardiac remodelling. The improved cardiac phenotype was associated with attenuation of heart and cardiomyocyte size, less cardiac fibrosis, lower expression of atrial and B-type natriuretic peptide genes, attenuation of profibrotic markers, and increased expression of p15 (a miR-154 target and cell cycle inhibitor). In summary, this study suggests that miR-154 may represent a novel target for the treatment of cardiac pathologies associated with cardiac fibrosis, hypertrophy and dysfunction.
Asunto(s)
Hipertrofia Ventricular Izquierda/genética , MicroARNs/antagonistas & inhibidores , MicroARNs/genética , Fibrosis Pulmonar/genética , Remodelación Ventricular/genética , Animales , Aorta/cirugía , Factor Natriurético Atrial/biosíntesis , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/biosíntesis , Modelos Animales de Enfermedad , Ecocardiografía , Hipertensión/patología , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/cirugía , Masculino , Ratones , Ratones Endogámicos C57BL , Péptido Natriurético Encefálico/biosíntesis , Oligonucleótidos/genética , Oligonucleótidos/farmacología , Remodelación Ventricular/efectos de los fármacosRESUMEN
Previous animal studies had shown that increasing heat shock protein 70 (Hsp70) using a transgenic, gene therapy or pharmacological approach provided cardiac protection in models of acute cardiac stress. Furthermore, clinical studies had reported associations between Hsp70 levels and protection against atrial fibrillation (AF). AF is the most common cardiac arrhythmia presenting in cardiology clinics and is associated with increased rates of heart failure and stroke. Improved therapies for AF and heart failure are urgently required. Despite promising observations in animal studies which targeted Hsp70, we recently reported that increasing Hsp70 was unable to attenuate cardiac dysfunction and pathology in a mouse model which develops heart failure and intermittent AF. Given our somewhat unexpected finding and the extensive literature suggesting Hsp70 provides cardiac protection, it was considered important to assess whether Hsp70 could provide protection in another mouse model of heart failure and AF. The aim of the current study was to determine whether increasing Hsp70 could attenuate adverse cardiac remodeling, cardiac dysfunction and episodes of arrhythmia in a mouse model of heart failure and AF due to overexpression of Muscle-Restricted Coiled-Coil (MURC). Cardiac function and pathology were assessed in mice at approximately 12 months of age. We report here, that chronic overexpression of Hsp70 was unable to provide protection against cardiac dysfunction, conduction abnormalities, fibrosis or characteristic molecular markers of the failing heart. In summary, elevated Hsp70 may provide protection in acute cardiac stress settings, but appears insufficient to protect the heart under chronic cardiac disease conditions.
Asunto(s)
Fibrilación Atrial/fisiopatología , Proteínas HSP70 de Choque Térmico/metabolismo , Insuficiencia Cardíaca/fisiopatología , Ventrículos Cardíacos/fisiopatología , Remodelación Ventricular , Animales , Fibrilación Atrial/metabolismo , Enfermedad Crónica , Colágeno Tipo I/metabolismo , Modelos Animales de Enfermedad , Electrocardiografía , Femenino , Fibrosis , Proteínas HSP70 de Choque Térmico/genética , Insuficiencia Cardíaca/metabolismo , Ventrículos Cardíacos/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas Musculares/genética , Miocardio/metabolismo , Miocardio/patología , Proteínas de Unión al GTP rho/metabolismo , Proteína de Unión al GTP rhoARESUMEN
Antigen-presenting cells survey their environment and present captured antigens bound to major histocompatibility complex (MHC) molecules. Formation of MHC-antigen complexes occurs in specialized compartments where multiple protein trafficking routes, still incompletely understood, converge. Autophagy is a route that enables the presentation of cytosolic antigen by MHC class II molecules. Some reports also implicate autophagy in the presentation of extracellular, endocytosed antigen by MHC class I molecules, a pathway termed "cross-presentation." The role of autophagy in cross-presentation is controversial. This may be due to studies using different types of antigen presenting cells for which the use of autophagy is not well defined. Here we report that active use of autophagy is evident only in DC subtypes specialized in cross-presentation. However, the contribution of autophagy to cross-presentation varied depending on the form of antigen: it was negligible in the case of cell-associated antigen or antigen delivered via receptor-mediated endocytosis, but more prominent when the antigen was a soluble protein. These findings highlight the differential use of autophagy and its machinery by primary cells equipped with specific immune function, and prompt careful reassessment of the participation of this endocytic pathway in antigen cross-presentation.
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Presentación de Antígeno/inmunología , Autofagia/inmunología , Reactividad Cruzada/inmunología , Células Dendríticas/metabolismo , Animales , Células Dendríticas/inmunología , Endocitosis/inmunología , Endocitosis/fisiología , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , RatonesRESUMEN
Traditionally, macroautophagy (autophagy) is viewed as a pathway of cell survival. Autophagy ensures the elimination of damaged or unwanted cytosolic components and provides a source of cellular nutrients during periods of stress. Interestingly, autophagy can also directly intersect with, and impact, other major pathways of cellular function. Here, we will review the contribution of autophagy to pathways of antigen presentation. The autophagy machinery acts to modulate both MHCI and MHCII antigen presentation. As such autophagy is an important participant in pathways that elicit host cell immunity and the elimination of infectious pathogens.