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BACKGROUND: The heart responds to hemodynamic overload through cardiac hypertrophy and activation of the fetal gene program. However, these changes have not been thoroughly examined in individual cardiomyocytes, and the relation between cardiomyocyte size and fetal gene expression remains elusive. We established a method of high-throughput single-molecule RNA imaging analysis of in vivo cardiomyocytes and determined spatial and temporal changes during the development of heart failure. METHODS AND RESULTS: We applied three novel single-cell analysis methods, namely, single-cell quantitative PCR (sc-qPCR), single-cell RNA sequencing (scRNA-seq), and single-molecule fluorescence in situ hybridization (smFISH). Isolated cardiomyocytes and cross sections from pressure overloaded murine hearts after transverse aortic constriction (TAC) were analyzed at an early hypertrophy stage (2â¯weeks, TAC2W) and at a late heart failure stage (8â¯weeks, TAC8W). Expression of myosin heavy chain ß (Myh7), a representative fetal gene, was induced in some cardiomyocytes in TAC2W hearts and in more cardiomyocytes in TAC8W hearts. Expression levels of Myh7 varied considerably among cardiomyocytes. Myh7-expressing cardiomyocytes were significantly more abundant in the middle layer, compared with the inner or outer layers of TAC2W hearts, while such spatial differences were not observed in TAC8W hearts. Expression levels of Myh7 were inversely correlated with cardiomyocyte size and expression levels of mitochondria-related genes. CONCLUSIONS: We developed a new image-analysis pipeline to allow automated and unbiased quantification of gene expression at the single-cell level and determined the spatial and temporal regulation of heterogenous Myh7 expression in cardiomyocytes after pressure overload.
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Aorta/diagnóstico por imagen , Cardiomegalia/genética , Insuficiencia Cardíaca/diagnóstico por imagen , Imagen Molecular/métodos , Cadenas Pesadas de Miosina/genética , Animales , Aorta/metabolismo , Aorta/patología , Cardiomegalia/diagnóstico , Cardiomegalia/diagnóstico por imagen , Regulación de la Expresión Génica/genética , Corazón/diagnóstico por imagen , Corazón/fisiopatología , Insuficiencia Cardíaca/patología , Hemodinámica , Hibridación Fluorescente in Situ , Ratones , Mitocondrias/genética , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Cadenas Pesadas de Miosina/aislamiento & purificación , ARN/genética , ARN/aislamiento & purificación , Análisis de Secuencia de ARN , Imagen Individual de Molécula , Análisis de la Célula IndividualRESUMEN
INTRODUCTION: Metabolomics has recently emerged as a tool for understanding comprehensive tumor-associated metabolic dysregulation. However, only limited application of this technology has been introduced into the clinical setting of breast cancer. OBJECTIVES: The aim of this study was to determine the feasibility of metabolome analysis using routine CNB/VAB samples from breast cancer patients and to elucidate metabolic signatures using metabolic profiling. METHODS: After breast cancer screenings, 20 consecutive patients underwent CNB/VAB, and diagnosed with benign, DCIS and IDC by histology. Metabolome analysis was performed using CE-MS. Differential metabolites were then analyzed and evaluated with MetaboAnalyst 4.0. RESULTS: We measured 116-targeted metabolites involved in energy metabolism. Principal component analysis and unsupervised hierarchical analysis revealed a distinct metabolic signature unique to namely "pure" IDC samples, whereas that of DCIS was similar to benign samples. Pathway analysis unveiled the most affected pathways of the "pure" IDC metabotype, including "pyrimidine," "alanine, aspartate, and glutamate" and "arginine and proline" pathways. CONCLUSIONS: Our proof-of-concept study demonstrated that CE-MS-based CNB/VAB metabolome analysis is feasible for implementation in routine clinical settings. The most affected pathways in this study may contribute to improved breast cancer stratification and precision medicine.
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Neoplasias de la Mama/metabolismo , Metabolómica , Adulto , Anciano , Anciano de 80 o más Años , Biopsia con Aguja , Neoplasias de la Mama/diagnóstico , Femenino , Humanos , Persona de Mediana Edad , Proyectos PilotoRESUMEN
The 83rdAnnual Scientific Meeting of the Japanese Circulation Society was held in Yokohama, Japan, on March 29-31, 2019, just as the cherry blossoms came into full bloom. Because the environment around cardiovascular healthcare is rapidly changing, it becomes highly important to make a breakthrough at the dawn of a new era. The main theme of this meeting was "Renaissance of Cardiology for the Creation of Future Medicine". The meeting benefited from the participation of 18,825 people, and there were in-depth and extensive discussions at every session, focusing on topics covering clinical and basic research, medical care provision system, human resource development, and public awareness in cardiovascular medicine. The meeting was completed with great success, and we greatly appreciate the tremendous cooperation and support from all affiliates.
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Investigación Biomédica/tendencias , Cardiología/tendencias , Enfermedades Cardiovasculares , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/terapia , Difusión de Innovaciones , HumanosRESUMEN
Marfan syndrome (MFS) is an autosomal dominant heritable disorder of connective tissue that affects the cardiovascular, skeletal, ocular, pulmonary, and nervous systems and is usually caused by mutations in the FBN1 gene, which encodes fibrillin-1. MFS is traditionally considered to result from the structural weakness of connective tissue. However, recent investigations on molecular mechanisms indicate that increased transforming growth factor-ß (TGF-ß) activity plays a crucial role in the pathogenesis of MFS and related disorders, such as Loeys-Dietz syndrome (LDS), which is caused by mutation in TGF-ß signaling-related genes. In addition, recent studies show that angiotensin II type 1 receptor (AT1R) signaling enhances cardiovascular pathologies in MFS, and the angiotensin II receptor blocker losartan has the potential to inhibit aortic aneurysm formation. However, the relationship between TGF-ß and AT1R signaling pathways remains poorly characterized. In this review, we discuss the recent studies on the molecular mechanisms underlying cardiovascular manifestations of MFS and LDS and the ensuing strategies for management.
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Aneurisma de la Aorta , Fibrilina-1/genética , Síndrome de Loeys-Dietz , Losartán/farmacología , Síndrome de Marfan , Factor de Crecimiento Transformador beta/metabolismo , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Aneurisma de la Aorta/etiología , Aneurisma de la Aorta/metabolismo , Aneurisma de la Aorta/fisiopatología , Aneurisma de la Aorta/prevención & control , Manejo de la Enfermedad , Humanos , Síndrome de Loeys-Dietz/complicaciones , Síndrome de Loeys-Dietz/tratamiento farmacológico , Síndrome de Loeys-Dietz/genética , Síndrome de Loeys-Dietz/fisiopatología , Síndrome de Marfan/complicaciones , Síndrome de Marfan/tratamiento farmacológico , Síndrome de Marfan/genética , Síndrome de Marfan/fisiopatología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genéticaRESUMEN
The transverse (t)-tubule system plays an essential role in healthy and diseased heart muscle, particularly in Ca(2+)-induced Ca(2+) release (CICR), and its structural disruption is an early event in heart failure. Both mechanical overload and unloading alter t-tubule structure, but the mechanisms mediating the normally tight regulation of the t-tubules in response to load variation are poorly understood. Telethonin (Tcap) is a stretch-sensitive Z-disc protein that binds to proteins in the t-tubule membrane. To assess its role in regulating t-tubule structure and function, we used Tcap knockout (KO) mice and investigated cardiomyocyte t-tubule and cell structure and CICR over time and following mechanical overload. In cardiomyocytes from 3-month-old KO (3mKO), there were isolated t-tubule defects and Ca(2+) transient dysynchrony without whole heart and cellular dysfunction. Ca(2+) spark frequency more than doubled in 3mKO. At 8 months of age (8mKO), cardiomyocytes showed progressive loss of t-tubules and remodelling of the cell surface, with prolonged and dysynchronous Ca(2+) transients. Ca(2+) spark frequency was elevated and the L-type Ca(2+) channel was depressed at 8 months only. After mechanical overload obtained by aortic banding constriction, the Ca(2+) transient was prolonged in both wild type and KO. Mechanical overload increased the Ca(2+) spark frequency in KO alone, where there was also significantly more t-tubule loss, with a greater deterioration in t-tubule regularity. In conjunction, Tcap KO showed severe loss of cell surface ultrastructure. These data suggest that Tcap is a critical, load-sensitive regulator of t-tubule structure and function.
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Corazón/fisiología , Proteínas Musculares/metabolismo , Miocitos Cardíacos/metabolismo , Sarcolema/metabolismo , Animales , Calcio/metabolismo , Señalización del Calcio , Conectina , Corazón/fisiopatología , Ratones , Ratones Noqueados , Proteínas Musculares/genética , Sarcolema/patologíaRESUMEN
Cardiac hypertrophy occurs as an adaptive response to increased workload to maintain cardiac function. However, prolonged cardiac hypertrophy causes heart failure, and its mechanisms are largely unknown. Here we show that cardiac angiogenesis is crucially involved in the adaptive mechanism of cardiac hypertrophy and that p53 accumulation is essential for the transition from cardiac hypertrophy to heart failure. Pressure overload initially promoted vascular growth in the heart by hypoxia-inducible factor-1 (Hif-1)-dependent induction of angiogenic factors, and inhibition of angiogenesis prevented the development of cardiac hypertrophy and induced systolic dysfunction. Sustained pressure overload induced an accumulation of p53 that inhibited Hif-1 activity and thereby impaired cardiac angiogenesis and systolic function. Conversely, promoting cardiac angiogenesis by introducing angiogenic factors or by inhibiting p53 accumulation developed hypertrophy further and restored cardiac dysfunction under chronic pressure overload. These results indicate that the anti-angiogenic property of p53 may have a crucial function in the transition from cardiac hypertrophy to heart failure.
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Gasto Cardíaco Bajo/fisiopatología , Cardiomegalia/fisiopatología , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/metabolismo , Animales , Aorta/patología , Aorta/fisiopatología , Presión Sanguínea , Cardiomegalia/patología , Circulación Coronaria , Progresión de la Enfermedad , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ratones , Neovascularización Patológica , Proteína p53 Supresora de Tumor/genéticaAsunto(s)
Amlodipino/administración & dosificación , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/prevención & control , Bloqueadores de los Canales de Calcio/administración & dosificación , Animales , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Enfermedad de la Arteria Coronaria/prevención & control , Sistemas de Liberación de Medicamentos , Humanos , Ratones , Medición de Riesgo , Factores de Riesgo , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Cardiovascular disease (CVD) is a global health burden in the world. Although low-carbohydrate diets (LCDs) have beneficial effects on CVD risk, their preventive effects remain elusive. We investigated whether LCDs ameliorate heart failure (HF) using a murine model of pressure overload. LCD with plant-derived fat (LCD-P) ameliorated HF progression, whereas LCD with animal-derived fat (LCD-A) aggravated inflammation and cardiac dysfunction. In the hearts of LCD-P-fed mice but not LCD-A, fatty acid oxidation-related genes were highly expressed, and peroxisome proliferator-activated receptor α (PPARα), which regulates lipid metabolism and inflammation, was activated. Loss- and gain-of-function experiments indicated the critical roles of PPARα in preventing HF progression. Stearic acid, which was more abundant in the serum and heart of LCD-P-fed mice, activated PPARα in cultured cardiomyocytes. We highlight the importance of fat sources substituted for reduced carbohydrates in LCDs and suggest that the LCD-P-stearic acid-PPARα pathway as a therapeutic target for HF.
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Enfermedades Cardiovasculares , Insuficiencia Cardíaca , Ratones , Animales , PPAR alfa/genética , PPAR alfa/metabolismo , Dieta Baja en Carbohidratos , InflamaciónRESUMEN
Pulmonary hypertension (PH) is a life-threatening disease characterized by a progressive narrowing of pulmonary arterioles. Although VEGF is highly expressed in lung of patients with PH and in animal PH models, the involvement of angiogenesis remains elusive. To clarify the pathophysiological function of angiogenesis in PH, we compared the angiogenic response in hypoxia (Hx) and SU5416 (a VEGFR2 inhibitor) plus Hx (SuHx) mouse PH models using 3D imaging. The 3D imaging analysis revealed an angiogenic response in the lung of the Hx-PH, but not of the severer SuHx-PH model. Selective VEGFR2 inhibition with cabozantinib plus Hx in mice also suppressed angiogenic response and exacerbated Hx-PH to the same extent as SuHx. Expression of endothelial proliferator-activated receptor γ coactivator 1α (PGC-1α) increased along with angiogenesis in lung of Hx-PH but not SuHx mice. In pulmonary endothelial cell-specific Ppargc1a-KO mice, the Hx-induced angiogenesis was suppressed, and PH was exacerbated along with increased oxidative stress, cellular senescence, and DNA damage. By contrast, treatment with baicalin, a flavonoid enhancing PGC-1α activity in endothelial cells, ameliorated Hx-PH with increased Vegfa expression and angiogenesis. Pulmonary endothelial PGC-1α-mediated angiogenesis is essential for adaptive responses to Hx and might represent a potential therapeutic target for PH.
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Hipertensión Pulmonar , Animales , Ratones , Senescencia Celular , Modelos Animales de Enfermedad , Daño del ADN , Células Endoteliales , Hipertensión Pulmonar/prevención & control , HipoxiaRESUMEN
Using the Cre-loxP system, we generated the first mouse model in which estrogen receptor-α non-nuclear signaling was inactivated in endothelial cells. Estrogen protection against mechanical vascular injury was impaired in this model. This result indicates the pivotal role of endothelial estrogen receptor-α non-nuclear signaling in the vasculoprotective effects of estrogen.
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Granulocyte colony-stimulating factor (G-CSF) was reported to induce myocardial regeneration by promoting mobilization of bone marrow stem cells to the injured heart after myocardial infarction, but the precise mechanisms of the beneficial effects of G-CSF are not fully understood. Here we show that G-CSF acts directly on cardiomyocytes and promotes their survival after myocardial infarction. G-CSF receptor was expressed on cardiomyocytes and G-CSF activated the Jak/Stat pathway in cardiomyocytes. The G-CSF treatment did not affect initial infarct size at 3 d but improved cardiac function as early as 1 week after myocardial infarction. Moreover, the beneficial effects of G-CSF on cardiac function were reduced by delayed start of the treatment. G-CSF induced antiapoptotic proteins and inhibited apoptotic death of cardiomyocytes in the infarcted hearts. G-CSF also reduced apoptosis of endothelial cells and increased vascularization in the infarcted hearts, further protecting against ischemic injury. All these effects of G-CSF on infarcted hearts were abolished by overexpression of a dominant-negative mutant Stat3 protein in cardiomyocytes. These results suggest that G-CSF promotes survival of cardiac myocytes and prevents left ventricular remodeling after myocardial infarction through the functional communication between cardiomyocytes and noncardiomyocytes.
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Factor Estimulante de Colonias de Granulocitos/farmacología , Infarto del Miocardio/fisiopatología , Miocitos Cardíacos/fisiología , Remodelación Ventricular/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Proteínas de Unión al ADN/biosíntesis , Activación Enzimática , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/metabolismo , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Movilización de Célula Madre Hematopoyética , Janus Quinasa 2 , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Proteínas Tirosina Quinasas/biosíntesis , Proteínas Proto-Oncogénicas/biosíntesis , Ratas , Receptores de Factor Estimulante de Colonias de Granulocito/biosíntesis , Factor de Transcripción STAT3 , Transducción de Señal , Factores de Tiempo , Transactivadores/biosíntesis , Función Ventricular/efectos de los fármacosAsunto(s)
Dinoprostona , Insuficiencia Cardíaca , Fibrosis , Corazón , Humanos , Transducción de SeñalRESUMEN
The underlying mechanisms of ventricular remodeling after myocardial infarction (MI) remain largely unknown. In this study, we performed an integrative analysis of spatial transcriptomics and single-nucleus RNA sequencing (snRNA-seq) in a murine MI model and found that mechanical stress-response genes are expressed at the border zone and play a critical role in left ventricular remodeling after MI. An integrative analysis of snRNA-seq and spatial transcriptome of the heart tissue after MI identified the unique cluster that appeared at the border zone in an early stage, highly expressing mechano-sensing genes, such as Csrp3. AAV9-mediated gene silencing and overexpression of Csrp3 demonstrated that upregulation of Csrp3 plays critical roles in preventing cardiac remodeling after MI by regulation of genes associated with mechano-sensing. Overall, our study not only provides an insight into spatiotemporal molecular changes after MI but also highlights that the mechano-sensing genes at the border zone act as adaptive regulators of left ventricular remodeling.
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Tissue fibrosis and organ dysfunction are hallmarks of age-related diseases including heart failure, but it remains elusive whether there is a common pathway to induce both events. Through single-cell RNA-seq, spatial transcriptomics, and genetic perturbation, we elucidate that high-temperature requirement A serine peptidase 3 (Htra3) is a critical regulator of cardiac fibrosis and heart failure by maintaining the identity of quiescent cardiac fibroblasts through degrading transforming growth factor-ß (TGF-ß). Pressure overload downregulates expression of Htra3 in cardiac fibroblasts and activated TGF-ß signaling, which induces not only cardiac fibrosis but also heart failure through DNA damage accumulation and secretory phenotype induction in failing cardiomyocytes. Overexpression of Htra3 in the heart inhibits TGF-ß signaling and ameliorates cardiac dysfunction after pressure overload. Htra3-regulated induction of spatio-temporal cardiac fibrosis and cardiomyocyte secretory phenotype are observed specifically in infarct regions after myocardial infarction. Integrative analyses of single-cardiomyocyte transcriptome and plasma proteome in human reveal that IGFBP7, which is a cytokine downstream of TGF-ß and secreted from failing cardiomyocytes, is the most predictable marker of advanced heart failure. These findings highlight the roles of cardiac fibroblasts in regulating cardiomyocyte homeostasis and cardiac fibrosis through the Htra3-TGF-ß-IGFBP7 pathway, which would be a therapeutic target for heart failure.
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Insuficiencia Cardíaca , Factor de Crecimiento Transformador beta , Fibroblastos/metabolismo , Fibrosis , Insuficiencia Cardíaca/metabolismo , Humanos , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismo , Factor de Crecimiento Transformador beta/metabolismoAsunto(s)
Cardiomegalia , Células Progenitoras Endoteliales , Insuficiencia Cardíaca , Neovascularización Fisiológica/fisiología , Fenómenos Biomecánicos/fisiología , Cardiomegalia/complicaciones , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatología , Supervivencia Celular , Células Progenitoras Endoteliales/fisiología , Células Progenitoras Endoteliales/trasplante , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/prevención & control , Humanos , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Estrés Fisiológico/fisiologíaRESUMEN
Most seven transmembrane receptors (7TMRs) are G protein-coupled receptors; however, some 7TMRs evoke intracellular signals through ß-arrestin as a biased receptor. As several ß-arrestin-biased agonists have been reported to be cardioprotective, we examined the role of the chemokine receptor CXCR7 as a ß-arrestin-biased receptor in the heart. Among 510 7TMR genes examined, Cxcr7 was the most abundantly expressed in the murine heart. Single-cell RNA-sequencing analysis revealed that Cxcr7 was abundantly expressed in cardiomyocytes and fibroblasts. Cardiomyocyte-specific Cxcr7 null mice showed more prominent cardiac dilatation and dysfunction than control mice 4 weeks after myocardial infarction. In contrast, there was no difference in cardiac phenotypes between fibroblast-specific Cxcr7-knockout mice and control mice even after myocardial infarction. TC14012, a specific agonist of CXCR7, significantly recruited ß-arrestin to CXCR7 in CXCR7-expressing cells and activated extracellular signal-regulated kinase (ERK) in neonatal rat cardiomyocytes. Cxcr7 expression was significantly increased and ERK was activated in the border zone of the heart in control, but not Cxcr7 null mice. These results indicate that the abundantly expressed CXCR7 in cardiomyocytes may play a protective role in the heart as a ß-arrestin-biased receptor and that CXCR7 may be a novel therapeutic target for myocardial infarction.
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Sistema de Señalización de MAP Quinasas , Infarto del Miocardio/metabolismo , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Receptores CXCR/metabolismo , beta-Arrestina 1/metabolismo , Animales , Ratones , Ratones Noqueados , Infarto del Miocardio/genética , Infarto del Miocardio/patología , Miocardio/patología , Miocitos Cardíacos/patología , Oligopéptidos/farmacología , Receptores CXCR/agonistas , Receptores CXCR/genética , beta-Arrestina 1/genéticaRESUMEN
Percutaneous coronary intervention (PCI) is sometimes considered as an alternative therapeutic strategy to surgical revascularization in patients with coronary artery disease (CAD) and reduced left ventricular ejection fraction (LVEF). However, the types or conditions of patients that receive the clinical benefit of left ventricular reverse remodelling (LVRR) remain unknown. The purpose of this study was to investigate the determinants of LVRR following PCI in CAD patients with reduced LVEF. From 4394 consecutive patients who underwent PCI, a total of 286 patients with reduced LV systolic function (LVEF < 50% at initial left ventriculography) were included in the analysis. LVRR was defined as LV end-systolic volume reduction ≥ 15% and improvement of LVEF ≥ 10% at 6 months follow-up left ventriculography. Patients were divided into LVRR (n = 63) and non-LVRR (n = 223) groups. Multivariate logistic regression analysis revealed that unprotected left main coronary artery (LMCA) intervention was significantly associated with LVRR (P = 0.007, odds ratios [OR] 4.70, 95% confidence interval [CI] 1.54-14.38), while prior PCI (P = 0.001, OR 0.35, 95% CI 0.19-0.66), presence of in-stent restenosis (P = 0.016, OR 0.32, 95% CI 0.12-0.81), and presence of de-novo stenosis (P = 0.038, OR 0.36, 95% CI 0.14-0.95) were negatively associated with LVRR. These data suggest the potential prognostic benefit of unprotected LMCA intervention for LVRR and importance of angiographic follow-up in patients with CAD and LV systolic dysfunction.
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Enfermedad de la Arteria Coronaria/fisiopatología , Enfermedad de la Arteria Coronaria/cirugía , Intervención Coronaria Percutánea , Sístole/fisiología , Remodelación Ventricular , Anciano , Enfermedad de la Arteria Coronaria/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Disfunción Ventricular IzquierdaRESUMEN
Increased transforming growth factor-ß (TGF-ß) signaling contributes to the pathophysiology of aortic aneurysm in Marfan syndrome (MFS). Recent reports indicate that a small but significant number of inflammatory cells are infiltrated into the aortic media and adventitia in MFS. However, little is known about the contribution of myeloid cells to aortic aneurysmal formation. In this study, we ablated the TGF-ß type II receptor gene Tgfbr2 in myeloid cells of Fbn1C1039G/+ MFS mice (Fbn1C1039G/+;LysM-Cre/+;Tgfbr2fl/fl mice, hereinafter called Fbn1C1039G/+;Tgfbr2MyeKO) and evaluated macrophage infiltration and TGF-ß signaling in the aorta. Aneurysmal formation with fragmentation and disarray of medial elastic fibers observed in MFS mice was significantly ameliorated in Fbn1C1039G/+;Tgfbr2MyeKO mice. In the aorta of Fbn1C1039G/+;Tgfbr2MyeKO mice, both canonical and noncanonical TGF-ß signals were attenuated and the number of infiltrated F4/80-positive macrophages was significantly reduced. In vitro, TGF-ß enhanced the migration capacity of RAW264.7 macrophages. These findings suggest that TGF-ß signaling in myeloid cells promotes aortic aneurysmal formation and its inhibition might be a novel therapeutic target in MFS.
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Aneurisma de la Aorta Torácica/patología , Síndrome de Marfan/patología , Receptor Tipo II de Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta2/metabolismo , Adventicia/citología , Animales , Aorta/patología , Línea Celular , Movimiento Celular , Proliferación Celular , Fibrilina-1/genética , Activación de Macrófagos/genética , Macrófagos/inmunología , Ratones , Ratones Noqueados , Células RAW 264.7 , Transducción de SeñalRESUMEN
Using genetically engineered mice lacking estrogen receptor-α non-nuclear signaling, this study demonstrated that estrogen receptor-α non-nuclear signaling activated myocardial cyclic guanosine monophosphate-dependent protein kinase G and conferred protection against cardiac remodeling induced by pressure overload. This pathway was indispensable to the therapeutic efficacy of cyclic guanosine monophosphate-phosphodiesterase 5 inhibition but not to that of soluble guanylate cyclase stimulation. These results might partially explain the equivocal results of phosphodiesterase 5 inhibitor efficacy and also provide the molecular basis for the advantage of using a soluble guanylate cyclase simulator as a new therapeutic option in post-menopausal women. This study also highlighted the need for female-specific therapeutic strategies for heart failure.