RESUMEN
Hypertrophic cardiomyopathy (HCM) is widely recognized as one of the most common inheritable cardiac disorders. Since its initial description over 60 years ago, advances in multimodality imaging and translational genetics have revolutionized our understanding of the disorder. The diagnosis and management of patients with HCM are optimized with a multidisciplinary approach. This, along with increased safety and efficacy of medical, percutaneous, and surgical therapies for HCM, has afforded more personalized care and improved outcomes for this patient population. In this review, we will discuss our modern understanding of the molecular pathophysiology that underlies HCM. We will describe the range of clinical presentations and discuss the role of genetic testing in diagnosis. Finally, we will summarize management strategies for the hemodynamic subtypes of HCM with specific emphasis on the rationale and evidence for the use of implantable cardioverter defibrillators, septal reduction therapy, and cardiac myosin inhibitors.
Asunto(s)
Cardiomiopatía Hipertrófica Familiar , Cardiomiopatía Hipertrófica , Desfibriladores Implantables , Humanos , Cardiomiopatía Hipertrófica Familiar/diagnóstico , Cardiomiopatía Hipertrófica Familiar/genética , Cardiomiopatía Hipertrófica Familiar/terapia , Cardiomiopatía Hipertrófica/diagnóstico , Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/terapia , Diagnóstico por ImagenRESUMEN
The adipose tissue-derived hormone leptin can drive decreases in food intake while increasing energy expenditure. In diet-induced obesity, circulating leptin levels rise proportionally to adiposity. Despite this hyperleptinemia, rodents and humans with obesity maintain increased adiposity and are resistant to leptin's actions. Here we show that inhibitors of the cytosolic enzyme histone deacetylase 6 (HDAC6) act as potent leptin sensitizers and anti-obesity agents in diet-induced obese mice. Specifically, HDAC6 inhibitors, such as tubastatin A, reduce food intake, fat mass, hepatic steatosis and improve systemic glucose homeostasis in an HDAC6-dependent manner. Mechanistically, peripheral, but not central, inhibition of HDAC6 confers central leptin sensitivity. Additionally, the anti-obesity effect of tubastatin A is attenuated in animals with a defective central leptin-melanocortin circuitry, including db/db and MC4R knockout mice. Our results suggest the existence of an HDAC6-regulated adipokine that serves as a leptin-sensitizing agent and reveals HDAC6 as a potential target for the treatment of obesity.
Asunto(s)
Histona Desacetilasa 6/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/farmacología , Leptina/metabolismo , Obesidad/metabolismo , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Peso Corporal , Dieta Alta en Grasa , Relación Dosis-Respuesta a Droga , Metabolismo Energético/efectos de los fármacos , Activación Enzimática , Regulación de la Expresión Génica/efectos de los fármacos , Histona Desacetilasa 6/genética , Histona Desacetilasa 6/metabolismo , Inhibidores de Histona Desacetilasas/química , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Ratones Obesos , Modelos Biológicos , Obesidad/tratamiento farmacológico , Obesidad/etiología , Transducción de Señal/efectos de los fármacosAsunto(s)
Fusobacterium necrophorum/aislamiento & purificación , Síndrome de Lemierre/diagnóstico , Clavícula/diagnóstico por imagen , Clavícula/patología , Trastornos de Deglución/etiología , Errores Diagnósticos , Femenino , Fiebre/etiología , Humanos , Síndrome de Lemierre/complicaciones , Síndrome de Lemierre/tratamiento farmacológico , Pulmón/diagnóstico por imagen , Pulmón/patología , Imagen por Resonancia Magnética , Osteomielitis/diagnóstico , Faringitis/etiología , Radiografía Torácica , Insuficiencia Respiratoria/etiología , Tomografía Computarizada por Rayos X , Adulto JovenAsunto(s)
Clavícula/microbiología , Síndrome de Lemierre/diagnóstico , Propionibacteriaceae/aislamiento & purificación , Antibacterianos/uso terapéutico , Trastornos de Deglución/etiología , Diagnóstico Diferencial , Femenino , Humanos , Síndrome de Lemierre/complicaciones , Síndrome de Lemierre/microbiología , Pulmón/diagnóstico por imagen , Pulmón/patología , Dolor/etiología , Trombocitopenia/complicaciones , Trombocitopenia/diagnóstico , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
CONTEXT: Pro-opiomelanocortin (POMC) and the melanocortin-4 receptor (MC4R) play a pivotal role in the leptin-melanocortin pathway. Mutations in these genes lead to monogenic types of obesity due to severe hyperphagia. In addition to dietary-induced obesity, a cardiac phenotype without hypertrophy has been identified in MC4R knockout mice. OBJECTIVE: We aimed to characterize cardiac morphology and function as well as tissue Na+ content in humans with mutations in POMC and MC4R genes. METHODS: A cohort of 42 patients (5 patients with bi-allelic POMC mutations, 6 heterozygous MC4R mutation carriers, 19 obese controls without known monogenic cause, and 12 normal weight controls) underwent cardiac magnetic resonance (CMR) imaging and 23Na-MRI. RESULTS: Monogenic obese patients with POMC or MC4R mutation respectively had a significantly lower left ventricular mass/body surface area (BSA) than nonmonogenic obese patients. Left ventricular end-diastolic volume/BSA was significantly lower in POMC- and MC4R-deficient patients than in nonmonogenic obese patients. Subcutaneous fat and skin Na+ content was significantly higher in POMC- and MC4R-deficient patients than in nonmonogenic obese patients. In these compartments, the water content was significantly higher in patients with POMC and MC4R mutation than in control groups. CONCLUSION: Patients with POMC or MC4R mutations carriers had a lack of transition to hypertrophy, significantly lower cardiac muscle mass/BSA, and stored more Na+ within the subcutaneous fat tissue than nonmonogenic obese patients. The results point towards the role of the melanocortin pathway for cardiac function and tissue Na+ storage and the importance of including cardiologic assessments into the diagnostic work-up of these patients.
Asunto(s)
Hipertrofia Ventricular Izquierda/etiología , Mutación , Proopiomelanocortina/genética , Receptor de Melanocortina Tipo 4/genética , Sodio/metabolismo , Función Ventricular Izquierda/fisiología , Adolescente , Agua Corporal/metabolismo , Femenino , Humanos , Hipertrofia Ventricular Izquierda/genética , Imagen por Resonancia Magnética , Masculino , Obesidad/complicaciones , Fenotipo , Proopiomelanocortina/fisiología , Receptor de Melanocortina Tipo 4/fisiologíaRESUMEN
Energy stores in fat tissue are determined in part by the activity of hypothalamic neurones expressing the melanocortin-4 receptor (MC4R). Even a partial reduction in MC4R expression levels in mice, rats or humans produces hyperphagia and morbid obesity. Thus, it is of great interest to understand the molecular basis of neuromodulation by the MC4R. The MC4R is a G protein-coupled receptor that signals efficiently through GαS , and this signalling pathway is essential for normal MC4R function in vivo. However, previous data from hypothalamic slice preparations indicated that activation of the MC4R depolarised neurones via G protein-independent regulation of the ion channel Kir7.1. In the present study, we show that deletion of Kcnj13 (ie, the gene encoding Kir7.1) specifically from MC4R neurones produced resistance to melanocortin peptide-induced depolarisation of MC4R paraventricular nucleus neurones in brain slices, resistance to the sustained anorexic effect of exogenously administered melanocortin peptides, late onset obesity, increased linear growth and glucose intolerance. Some MC4R-mediated phenotypes appeared intact, including Agouti-related peptide-induced stimulation of food intake and MC4R-mediated induction of peptide YY release from intestinal L cells. Thus, a subset of the consequences of MC4R signalling in vivo appears to be dependent on expression of the Kir7.1 channel in MC4R cells.
Asunto(s)
Hipotálamo/fisiopatología , Neuronas/fisiología , Obesidad/fisiopatología , Canales de Potasio de Rectificación Interna/fisiología , Receptor de Melanocortina Tipo 4/fisiología , Animales , Conducta Alimentaria/fisiología , Femenino , Masculino , Potenciales de la Membrana , Ratones Endogámicos C57BL , Ratones Noqueados , Canales de Potasio de Rectificación Interna/genéticaRESUMEN
Like most homeostatic systems, adiposity in mammals is defended between upper and lower boundary conditions. While leptin and melanocortin-4 receptor (MC4R) signaling are required for defending energy set point, mechanisms controlling upper and lower homeostatic boundaries are less well understood. In contrast to the MC4R, deletion of the MC3R does not produce measurable hyperphagia or hypometabolism under normal conditions. However, we demonstrate that MC3R is required bidirectionally for controlling responses to external homeostatic challenges, such as caloric restriction or calorie-rich diet. MC3R is also required for regulated excursion from set point, or rheostasis, during pregnancy. Further, we demonstrate a molecular mechanism: MC3R provides regulatory inputs to melanocortin signaling, acting presynaptically on agouti-related protein neurons to regulate γ-aminobutyric acid release onto anorexigenic MC4R neurons, exerting boundary control on the activity of MC4R neurons. Thus, the MC3R is a critical regulator of boundary controls on melanocortin signaling, providing rheostatic control on energy storage.
Asunto(s)
Metabolismo Energético , Conducta Alimentaria , Homeostasis , Potenciales Postsinápticos Inhibidores/fisiología , Neuronas/fisiología , Receptor de Melanocortina Tipo 3/fisiología , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
The family of inward rectifying potassium channels (Kir channels) plays crucial roles in the regulation of heart rhythms, renal excretion, insulin release, and neuronal activity. Their dysfunction has been attributed to numerous diseases such as cardiac arrhythmia, kidney failure and electrolyte imbalance, diabetes mellitus, epilepsy, retinal degeneration, and other neuronal disorders. We have recently demonstrated that the melanocortin-4 receptor (MC4R), a Gαs-coupled GPCR, regulates Kir7.1 activity through a mechanism independent of Gαs and cAMP. In contrast to the many other members of the Kir channel family, less is known about the biophysical properties, regulation, and physiological functions of Kir7.1. In addition to using conventional patch clamp techniques, we have employed a high-throughput Tl+ flux assay to further investigate the kinetics of MC4R-Kir7.1 signaling in vitro. Here, we discuss the employment of the Tl+ flux assay to study MC4R -mediated regulation of Kir7.1 activity and to screen compounds for drug discovery.
Asunto(s)
Canales de Potasio de Rectificación Interna/metabolismo , Receptor de Melanocortina Tipo 4/metabolismo , Talio/química , AMP Cíclico/metabolismo , Subunidades alfa de la Proteína de Unión al GTP/metabolismo , Regulación de la Expresión Génica , Células HEK293 , Humanos , Técnicas de Placa-Clamp , Canales de Potasio de Rectificación Interna/genética , Unión Proteica , Transducción de SeñalRESUMEN
Haploinsufficiency of the melanocortin-4 receptor, the most common monogenetic obesity syndrome in humans, is associated with a reduction in autonomic tone, bradycardia, and incidence of obesity-associated hypertension. Thus, it has been assumed that melanocortin obesity syndrome may be protective with respect to obesity-associated cardiovascular disease. We show here that absence of the melanocortin-4 receptor (MC4R) in mice causes dilated cardiomyopathy, characterized by reduced contractility and increased left ventricular diameter. This cardiomyopathy is independent of obesity as weight matched diet induced obese mice do not display systolic dysfunction. Mc4r cardiomyopathy is characterized by ultrastructural changes in mitochondrial morphology and cardiomyocyte disorganization. Remarkably, testing of myocardial tissue from Mc4r-/- mice exhibited increased ADP stimulated respiratory capacity. However, this increase in respiration correlates with increased reactive oxygen species production - a canonical mediator of tissue damage. Together this study identifies MC4R deletion as a novel and potentially clinically important cause of heart failure.
Asunto(s)
Cardiomiopatía Dilatada/genética , Cardiomiopatía Dilatada/patología , Receptor de Melanocortina Tipo 4/deficiencia , Adenosina Difosfato/metabolismo , Animales , Respiración de la Célula/efectos de los fármacos , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias/ultraestructura , Miocardio/patología , Miocitos Cardíacos/patología , Especies Reactivas de Oxígeno/metabolismo , Especies Reactivas de Oxígeno/toxicidadRESUMEN
The melanocortin peptides derived from pro-opiomelanocortin (POMC) were originally understood in terms of the biological actions of α-melanocyte-stimulating hormone (α-MSH) on pigmentation and adrenocorticotrophic hormone on adrenocortical glucocorticoid production. However, the discovery of POMC mRNA and melanocortin peptides in the CNS generated activities directed at understanding the direct biological actions of melanocortins in the brain. Ultimately, discovery of unique melanocortin receptors expressed in the CNS, the melanocortin-3 (MC3R) and melanocortin-4 (MC4R) receptors, led to the development of pharmacological tools and genetic models leading to the demonstration that the central melanocortin system plays a critical role in the regulation of energy homeostasis. Indeed, mutations in MC4R are now known to be the most common cause of early onset syndromic obesity, accounting for 2-5% of all cases. This review discusses the history of these discoveries, as well as the latest work attempting to understand the molecular and cellular basis of regulation of feeding and energy homeostasis by the predominant melanocortin peptide in the CNS, α-MSH.
Asunto(s)
Metabolismo Energético , Conducta Alimentaria , Homeostasis , alfa-MSH/metabolismo , Proteína Relacionada con Agouti/metabolismo , Animales , Clonación Molecular , Metabolismo Energético/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Homeostasis/efectos de los fármacos , Humanos , Proteínas de la Membrana/metabolismo , Neuronas/metabolismo , Optogenética/métodos , Proopiomelanocortina/metabolismo , Isoformas de Proteínas , Receptores de Melanocortina/genética , Receptores de Melanocortina/metabolismo , Transducción de Señal , alfa-MSH/farmacologíaRESUMEN
Recent successes in deriving human-induced pluripotent stem cells (hiPSCs) allow for the possibility of studying human neurons derived from patients with neurological diseases. Concomitant inhibition of the BMP and TGF-ß1 branches of the TGF-ß signaling pathways by the endogenous antagonist, Noggin, and the small molecule SB431542, respectively, induces efficient neuralization of hiPSCs, a method known as dual-SMAD inhibition. The use of small molecule inhibitors instead of their endogenous counterparts has several advantages including lower cost, consistent activity, and the maintenance of xeno-free culture conditions. We tested the efficacy of DMH1, a highly selective small molecule BMP-inhibitor for its potential to replace Noggin in the neuralization of hiPSCs. We compare Noggin and DMH1-induced neuralization of hiPSCs by measuring protein and mRNA levels of pluripotency and neural precursor markers over a period of seven days. The regulation of five of the six markers assessed was indistinguishable in the presence of concentrations of Noggin or DMH1 that have been shown to effectively inhibit BMP signaling in other systems. We observed that by varying the DMH1 or Noggin concentration, we could selectively modulate the number of SOX1 expressing cells, whereas PAX6, another neural precursor marker, remained the same. The level and timing of SOX1 expression have been shown to affect neural induction as well as neural lineage. Our observations, therefore, suggest that BMP-inhibitor concentrations need to be carefully monitored to ensure appropriate expression levels of all transcription factors necessary for the induction of a particular neuronal lineage. We further demonstrate that DMH1-induced neural progenitors can be differentiated into ß3-tubulin expressing neurons, a subset of which also express tyrosine hydroxylase. Thus, the combined use of DMH1, a highly specific BMP-pathway inhibitor, and SB431542, a TGF-ß1-pathway specific inhibitor, provides us with the tools to independently regulate these two pathways through the exclusive use of small molecule inhibitors.