RESUMO
Atrial myopathy is a condition that consists of electrical, structural, contractile, and autonomic remodeling of the atria and is the substrate for development of atrial fibrillation, the most common arrhythmia. Pathophysiologic mechanisms driving atrial myopathy are inflammation, oxidative stress, atrial stretch, and neurohormonal signals, e.g., angiotensin-II and aldosterone. These mechanisms initiate the structural and functional remodeling of the atrial myocardium. Novel therapeutic strategies are being developed that target the pathophysiologic mechanisms of atrial myopathy. In this review, we will discuss the pathophysiology of atrial myopathy, as well as diagnostic and therapeutic strategies.
Assuntos
Fibrilação Atrial , Remodelamento Atrial , Doenças Musculares , Humanos , Relevância Clínica , Átrios do Coração , Miocárdio , Remodelamento Atrial/fisiologiaRESUMO
Dysfunction or failure of the endothelial organ is a heterogenous and often ill-described feature of both cardiovascular and noncardiovascular disorders. Although seldom recognized as a separate clinical condition, endothelial cell dysfunction (ECD) is an established catalyst of disease. However, even in recent pathophysiological studies, ECD is frequently oversimplified as a binary state without gradation, based on the assessment of a single function (e.g., synthesis or activity of nitric oxide) and without considering spatiotemporal dimensions (local vs. generalized, acute vs. chronic). In this article, we suggest a simple scale to grade the severity of ECD and a definition of ECD in three dimensions: space, time, and severity. We also adopt a broader perspective on ECD by integrating and comparing gene expression data of endothelial cells from different organs and diseases and propose a concept that links common pathophysiological mechanisms. We hope that this will enhance the understanding of the pathophysiology of ECD and stimulate discussion in this field.
Assuntos
Células Endoteliais , Doenças Vasculares , Humanos , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Óxido Nítrico/metabolismoRESUMO
Cardiac arrhythmias are associated with cardiovascular morbidity and mortality. Cardiac electrophysiology studies (EPS) use intracardiac catheter recording and stimulation for profound evaluation of the heart's electrical properties. The main clinical application is investigation and treatment of rhythm disorders. These techniques have been translated to the murine setting to open opportunities for detailed evaluation of the impact of different characteristics (including genetics) and interventions on cardiac electrophysiology and -pathology. Currently, a detailed description of the technique of murine transjugular EPS (which is the standard route of catheter introduction) is lacking. This article provides detailed information on EPS in mice via the transjugular route. This includes catheter placement, stimulation protocols, intracardiac tracing interpretation, artifact reduction, and surface ECG recording. In addition, reference values as obtained in C57BL/6N mice are presented for common electrophysiological parameters. This detailed methodological description aims to increase accessibility and standardization of EPS in mice. Ultimately, also human research and patient care may benefit from translation of the knowledge obtained in preclinical models using this technique.NEW & NOTEWORTHY Electrophysiology studies (EPS) allow in-depth evaluation of cardiac electrophysiology and -pathology. These techniques have been adapted to the murine setting for (translational) studies, mainly focusing on arrhythmogenesis. Despite the frequent application of EPS via the transjugular route, a thorough description of the technique is currently lacking. This article aims to function as a comprehensive guide, also elaborating (for the first time) on nonsurgical aspects such as catheter positioning, tracing artifacts, stimulation protocols, and reference values.
Assuntos
Arritmias Cardíacas , Técnicas Eletrofisiológicas Cardíacas , Animais , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas/métodos , Coração , Humanos , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Endothelial cells (ECs) secrete different paracrine signals that modulate the function of adjacent cells; two examples of these paracrine signals are nitric oxide (NO) and neuregulin-1 (NRG1), a cardioprotective growth factor. Currently, it is undetermined whether one paracrine factor can compensate for the loss of another. Herein, we hypothesized that NRG1 can compensate for endothelial NO synthase (eNOS) deficiency. We characterized eNOS null and wild-type (WT) mice by cardiac ultrasound and histology and we determined circulating NRG1 levels. In a separate experiment, eight groups of mice were divided into four groups of eNOS null mice and WT mice; half of the mice received angiotensin II (ANG II) to induce a more severe phenotype. Mice were randomized to daily injections with NRG1 or vehicle for 28 days. eNOS deficiency increased NRG1 plasma levels, indicating that ECs increase their NRG1 expression when NO production is deleted. eNOS deficiency also increased blood pressure, lowered heart rate, induced cardiac fibrosis, and affected diastolic function. In eNOS null mice, ANG II administration not only increased cardiac fibrosis but also induced cardiac hypertrophy and renal fibrosis. NRG1 administration prevented cardiac and renal hypertrophy and fibrosis caused by ANG II infusion and eNOS deficiency. Moreover, Nrg1 expression in the myocardium is shown to be regulated by miR-134. This study indicates that administration of endothelium-derived NRG1 can compensate for eNOS deficiency in the heart and kidneys.NEW & NOTEWORTHY ECs compensate for eNOS deficiency by increasing the secretion of NRG1. NRG1 administration prevents cardiac and renal hypertrophy and fibrosis caused by ANG II infusion and eNOS deficiency. NRG1 expression is regulated by miR-134.
Assuntos
Células Endoteliais/metabolismo , Frequência Cardíaca/genética , Coração/efeitos dos fármacos , MicroRNAs/metabolismo , Miocárdio/patologia , Neuregulina-1/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico/metabolismo , Angiotensina II/farmacologia , Animais , Cardiomegalia/genética , Cardiomegalia/patologia , Diástole/efeitos dos fármacos , Fibrose/genética , Fibrose/patologia , Regulação da Expressão Gênica , Frequência Cardíaca/efeitos dos fármacos , Rim/patologia , Camundongos , Camundongos Knockout , Neuregulina-1/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Distribuição Aleatória , Vasoconstritores/farmacologiaRESUMO
The myocardium is a highly structured pluricellular tissue which is governed by an intricate network of intercellular communication. Endothelial cells are the most abundant cell type in the myocardium and exert crucial roles in both healthy myocardium and during myocardial disease. In the last decade, microRNAs have emerged as new actors in the regulation of cellular function in almost every cell type. Here, we review recent evidence on the regulatory function of different microRNAs expressed in endothelial cells, also called endothelial microRNAs, in healthy and diseased myocardium. Endothelial microRNA emerged as modulators of angiogenesis in the myocardium, they are implicated in the paracrine role of endothelial cells in regulating cardiac contractility and homeostasis, and interfere in the crosstalk between endothelial cells and cardiomyocytes.
Assuntos
Doenças Cardiovasculares/genética , Células Endoteliais/metabolismo , MicroRNAs/metabolismo , Miocárdio/metabolismo , Animais , Humanos , MicroRNAs/genética , Miocárdio/patologia , Neovascularização Fisiológica/genética , Comunicação Parácrina/genéticaRESUMO
Neuregulin-1 (NRG1) is a paracrine growth factor, secreted by cardiac endothelial cells (ECs) in conditions of cardiac overload/injury. The current concept is that the cardiac effects of NRG1 are mediated by activation of erythroblastic leukemia viral oncogene homolog (ERBB)4/ERBB2 receptors on cardiomyocytes. However, recent studies have shown that paracrine effects of NRG1 on fibroblasts and macrophages are equally important. Here, we hypothesize that NRG1 autocrine signaling plays a role in cardiac remodeling. We generated EC-specific Erbb4 knockout mice to eliminate endothelial autocrine ERBB4 signaling without affecting paracrine NRG1/ERBB4 signaling in the heart. We first observed no basal cardiac phenotype in these mice up to 32 wk. We next studied these mice following transverse aortic constriction (TAC), exposure to angiotensin II (ANG II), or myocardial infarction in terms of cardiac performance, myocardial hypertrophy, myocardial fibrosis, and capillary density. In general, no major differences between EC-specific Erbb4 knockout mice and control littermates were observed. However, 8 wk following TAC both myocardial hypertrophy and fibrosis were attenuated by EC-specific Erbb4 deletion, albeit these responses were normalized after 20 wk. Similarly, 4 wk after ANG II treatment, myocardial fibrosis was less pronounced compared with control littermates. These observations were supported by RNA-sequencing experiments on cultured endothelial cells showing that NRG1 controls the expression of various hypertrophic and fibrotic pathways. Overall, this study shows a role of endothelial autocrine NRG1/ERBB4 signaling in the modulation of hypertrophic and fibrotic responses during early cardiac remodeling. This study contributes to understanding the spatiotemporal heterogeneity of myocardial autocrine and paracrine responses following cardiac injury.NEW & NOTEWORTHY The role of NRG1/ERBB signaling in endothelial cells is not completely understood. Our study contributes to the understanding of spatiotemporal heterogeneity of myocardial autocrine and paracrine responses following cardiac injury and shows a role of endothelial autocrine NRG1/ERBB4 signaling in the modulation of hypertrophic and fibrotic responses during early cardiac remodeling.
Assuntos
Comunicação Autócrina , Cardiomiopatias/metabolismo , Células Endoteliais/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Neuregulina-1/metabolismo , Receptor ErbB-4/metabolismo , Função Ventricular Esquerda , Remodelação Ventricular , Animais , Cardiomiopatias/genética , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Células Cultivadas , Modelos Animais de Doenças , Fibrose , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miócitos Cardíacos/patologia , Neovascularização Fisiológica , Comunicação Parácrina , Receptor ErbB-4/deficiência , Receptor ErbB-4/genética , Transdução de SinaisRESUMO
An important physiological role of the aorta is to convert the pulsatile blood flow that originates in the heart to a nearly continuous flow in the peripheral vessels. Previously, we demonstrated that basal, unstimulated nitric oxide (NO) production is more abundant in large as compared with muscular arteries and that it is an important regulator of arterial (aortic) stiffness. Hence, endothelial function and NO bioavailability are important determinants of aortic biomechanics, and mouse models with altered NO signaling might be of interest to investigate the (patho)physiological role of the NO signaling as a dynamic regulator of arterial stiffness. We aimed to characterize the ex vivo biomechanical properties of aortic segments from mice with no (eNOS-/-), normal [wild type (WT)], or high (eNOS-tg) endothelial NO synthase (eNOS) expression. Isobaric aortic diameter and compliance were lower in eNOS-/- mice and increased in eNOS-tg mice as compared with WT mice. Interestingly, these differences remained when NO levels were pharmacologically restored ex vivo, suggesting that they were not merely the result of a lack or excess of the vasodilator effects of NO. Analysis of basal vascular smooth muscle cell tone and the phasic as well as the tonic contraction in response to α1-adrenergic stimulation with phenylephrine revealed that the chronic lack of eNOS expression affected aortic reactivity similarly but with different magnitude as compared with acute eNOS blockade using Nω-nitro-l-arginine methyl ester in WT and eNOS-tg mice, suggesting that chronical distortion of NO signaling triggered several compensatory mechanisms that reflect the organism's attempt to restore the contractile imbalance and maintain optimal central hemodynamics.NEW & NOTEWORTHY Endothelial function and NO bioavailability are important determinants of aortic biomechanics and function. With a new technique we investigated the ex vivo aortic segment biomechanics of different mouse models with altered NO signaling. Our experiments clearly show that chronic distortion of NO signaling triggered several compensatory mechanisms that reflect the organism's attempt to maintain optimal central hemodynamics.
Assuntos
Aorta/fisiologia , Óxido Nítrico Sintase Tipo III/metabolismo , Rigidez Vascular , Animais , Aorta/metabolismo , Fenômenos Biomecânicos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tono Muscular , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Transdução de Sinais , VasoconstriçãoRESUMO
RATIONALE: Increased titin-dependent cardiomyocyte tension is a hallmark of heart failure with preserved ejection fraction associated with type-2 diabetes mellitus. However, the insulin-related signaling pathways that modify titin-based cardiomyocyte tension, thereby contributing to modulation of diastolic function, are largely unknown. OBJECTIVE: We aimed to determine how impaired insulin signaling affects titin expression and phosphorylation and thus increases passive cardiomyocyte tension, and whether metformin or neuregulin-1 (NRG-1) can correct disturbed titin modifications and increased titin-based stiffness. METHODS AND RESULTS: We used cardiac biopsies from human diabetic (n=23) and nondiabetic patients (n=19), cultured rat cardiomyocytes, left ventricular tissue from apolipoprotein E-deficient mice with streptozotocin-induced diabetes mellitus (n=12-22), and ZSF1 (obese diabetic Zucker fatty/spontaneously hypertensive heart failure F1 hybrid) rats (n=5-6) and analyzed insulin-dependent signaling pathways that modulate titin phosphorylation. Titin-based passive tension was measured using permeabilized cardiomyocytes. In human diabetic hearts, we detected titin hypophosphorylation at S4099 and hyperphosphorylation at S11878, suggesting altered activity of protein kinases; cardiomyocyte passive tension was significantly increased. When applied to cultured cardiomyocytes, insulin and metformin increased titin phosphorylation at S4010, S4099, and S11878 via enhanced ERK1/2 (extracellular signal regulated kinase 1/2) and PKCα (protein kinase Cα) activity; NRG-1 application enhanced ERK1/2 activity but reduced PKCα activity. In apolipoprotein E-deficient mice, chronic treatment of streptozotocin-induced diabetes mellitus with NRG-1 corrected titin phosphorylation via increased PKG (protein kinase G) and ERK1/2 activity and reduced PKCα activity, which reversed the diabetes mellitus-associated changes in titin-based passive tension. Acute application of NRG-1 to obese ZSF1 rats with type-2 diabetes mellitus reduced end-diastolic pressure. CONCLUSIONS: Mechanistically, we found that impaired cGMP-PKG signaling and elevated PKCα activity are key modulators of titin-based cardiomyocyte stiffening in diabetic hearts. We conclude that by restoring normal kinase activities of PKG, ERK1/2, and PKCα, and by reducing cardiomyocyte passive tension, chronic NRG-1 application is a promising approach to modulate titin properties in heart failure with preserved ejection fraction associated with type-2 diabetes mellitus.
Assuntos
Conectina/metabolismo , Cardiomiopatias Diabéticas/metabolismo , Insulina/farmacologia , Miócitos Cardíacos/metabolismo , Neuregulina-1/farmacologia , Processamento de Proteína Pós-Traducional , Transdução de Sinais , Animais , Células Cultivadas , GMP Cíclico/metabolismo , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Fosforilação , Proteína Quinase C-alfa/metabolismo , Ratos , Ratos ZuckerRESUMO
Randomized clinical trials initially used heart failure (HF) patients with low left ventricular ejection fraction (LVEF) to select study populations with high risk to enhance statistical power. However, this use of LVEF in clinical trials has led to oversimplification of the scientific view of a complex syndrome. Descriptive terms such as 'HFrEF' (HF with reduced LVEF), 'HFpEF' (HF with preserved LVEF), and more recently 'HFmrEF' (HF with mid-range LVEF), assigned on arbitrary LVEF cut-off points, have gradually arisen as separate diseases, implying distinct pathophysiologies. In this article, based on pathophysiological reasoning, we challenge the paradigm of classifying HF according to LVEF. Instead, we propose that HF is a heterogeneous syndrome in which disease progression is associated with a dynamic evolution of functional and structural changes leading to unique disease trajectories creating a spectrum of phenotypes with overlapping and distinct characteristics. Moreover, we argue that by recognizing the spectral nature of the disease a novel stratification will arise from new technologies and scientific insights that will shape the design of future trials based on deeper understanding beyond the LVEF construct alone.
Assuntos
Insuficiência Cardíaca/classificação , Volume Sistólico , Comorbidade , Progressão da Doença , Endotélio Vascular/fisiopatologia , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Miócitos Cardíacos/fisiologia , Valores de Referência , Disfunção Ventricular Esquerda/fisiopatologia , Remodelação VentricularRESUMO
Cardiac microvascular endothelial cells (CMVECs) are the most numerous cells in the myocardium and orchestrate cardiogenesis during development, regulate adult cardiac function, and modulate pathophysiology of heart failure. It has been shown that the transcriptome of CMVECs differs from other endothelial cell types, but transcriptomic changes in cardiac endothelial cells during cardiac maturation and cardiac remodeling have not been studied. CMVECs were isolated from rat hearts based on CD31 expression and were immediately processed for RNA sequencing. We compared gene expression levels from primary CMVECs of neonatal hearts, normal adult hearts, and infarcted hearts. Between neonatal and adult CMVECs, 6,838 genes were differentially expressed, indicating that CMVECs undergo a substantial transformation during postnatal cardiac growth. A large fraction of genes upregulated in neonatal CMVECs are part of mitosis pathways, whereas a large fraction of genes upregulated in adult CMVECs are part of cellular response, secretory, signaling, and cell adhesion pathways. Between CMVECs of normal adult hearts and infarcted hearts, 159 genes were differentially expressed. We found a limited degree of overlap (55 genes) between the differentially expressed genes in neonatal and infarcted-hearts. Of 46 significantly upregulated genes in the infarcted heart, 46% were also upregulated in neonatal hearts relative to sham. Of 113 significantly downregulated genes in the infarcted-hearts, 30% were also downregulated in neonatal hearts relative to sham. These data demonstrate that CMVECs undergo dramatic changes from neonatal to adult and more subtle changes between normal state and cardiac remodeling.
Assuntos
Células Endoteliais/metabolismo , Coração/fisiologia , Transcriptoma/genética , Remodelação Ventricular/genética , Animais , Adesão Celular/genética , Células Cultivadas , Regulação para Baixo/genética , Feminino , Perfilação da Expressão Gênica/métodos , Miocárdio/metabolismo , Ratos , Ratos Sprague-Dawley , Análise de Sequência de RNA/métodos , Transdução de Sinais/genética , Regulação para Cima/genéticaRESUMO
The myocardium is a highly structured tissue consisting of different cell types including cardiomyocytes, endothelial cells, fibroblasts, smooth muscle cells, inflammatory cells, and stem cells. Microvascular endothelial cells are the most abundant cell type in the myocardium and play crucial roles during cardiac development, in normal adult myocardium, and during myocardial diseases such as heart failure. In the last decade, epigenetic changes have been described regulating cellular function in almost every cell type in the organism. Here, we review recent evidence on different epigenetic changes that regulate intercellular communication in normal myocardium and during myocardial diseases, including cardiac remodeling. Epigenetic changes influence many intercellular communication signaling systems, including the nitric oxide, angiotensin, and endothelin signaling systems. In this review, we go beyond discussing classic endothelial function (for instance nitric oxide secretion) and will discuss epigenetic regulation of intercellular communication.
Assuntos
Comunicação Celular/genética , Metilação de DNA , Epigênese Genética , Cardiopatias/genética , Miocárdio/metabolismo , Remodelação Ventricular/genética , Acetilação , Angiotensinas/genética , Angiotensinas/metabolismo , Animais , Montagem e Desmontagem da Cromatina , Endotelinas/genética , Endotelinas/metabolismo , Fibrose , Regulação da Expressão Gênica , Cardiopatias/metabolismo , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Histonas/genética , Histonas/metabolismo , Humanos , Miocárdio/patologia , Óxido Nítrico/metabolismo , Transdução de SinaisRESUMO
Anthracycline chemotherapy has a prominent role in treating many forms of cancer. Unfortunately, cardiotoxic side effects represent a serious limitation to their use, with doxorubicin being the leading drug of the group. Indeed, anthracycline-induced cardiomyopathy is an important public health concern because it may not be detected for many years and remains a lifelong threat. Even after decades of investigation, neither the exact mode of action of anthracyclines nor the pathways leading to their side effect are fully understood. It is increasingly important to establish collaboration between oncologists and cardiologists to improve the management of cancer patient receiving anthracyclines. This article reviews the clinical course, pathogenesis, cardiac monitoring and new concepts in diagnosing and preventing anthracycline-induced cardiotoxicity.
Assuntos
Antraciclinas/efeitos adversos , Cardiotoxicidade/prevenção & controle , Cardiotoxicidade/fisiopatologia , Animais , Antineoplásicos/efeitos adversos , Cardiotoxicidade/etiologia , Cardiotoxicidade/metabolismo , HumanosRESUMO
We have previously shown that treatment with recombinant human neuregulin-1 (rhNRG-1) improves pulmonary arterial hypertension (PAH) in a monocrotaline (MCT)-induced animal model, by decreasing pulmonary arterial remodelling and endothelial dysfunction, as well as by restoring right ventricular (RV) function. Additionally, rhNRG-1 treatment showed direct myocardial anti-remodelling effects in a model of pressure loading of the RV without PAH. This work aimed to study the intrinsic cardiac effects of rhNRG-1 on experimental PAH and RV pressure overload, and more specifically on diastolic stiffness, at both the ventricular and cardiomyocyte level. We studied the effects of chronic rhNRG-1 treatment on ventricular passive stiffness in RV and LV samples from MCT-induced PAH animals and in the RV from animals with compensated and decompensated RV hypertrophy, through a mild and severe pulmonary artery banding (PAB). We also measured passive tension in isolated cardiomyocytes and quantified the expression of myocardial remodelling-associated genes and calcium handling proteins. Chronic rhNRG-1 treatment decreased passive tension development in RV and LV isolated from animals with MCT-induced PAH. This decrease was associated with increased phospholamban phosphorylation, and with attenuation of the expression of cardiac maladaptive remodelling markers. Finally, we showed that rhNRG-1 therapy decreased RV remodelling and cardiomyocyte passive tension development in PAB-induced RV hypertrophy animals, without compromising cardiac function, pointing to cardiac-specific effects in both hypertrophy stages. In conclusion, we demonstrated that rhNRG-1 treatment decreased RV intrinsic diastolic stiffness, through the improvement of calcium handling and cardiac remodelling signalling.
Assuntos
Diástole/fisiologia , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Neuregulina-1/farmacologia , Rigidez Vascular/efeitos dos fármacos , Disfunção Ventricular Direita/tratamento farmacológico , Animais , Sinalização do Cálcio/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Neuregulina-1/uso terapêutico , Ratos , Ratos Wistar , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Remodelação Ventricular/efeitos dos fármacosRESUMO
The neuregulin-1 (NRG-1)/receptor tyrosine-protein kinase erbB (ErbB) system is an endothelium-controlled paracrine system modulating cardiac performance and adaptation. Recent studies have indicated that NRG-1 has antifibrotic effects in the left ventricle, which were explained by direct actions on cardiac fibroblasts. However, the NRG-1/ErbB system also regulates the function of macrophages. In this study, we hypothesized that the antifibrotic effect of NRG-1 in the heart is at least partially mediated through inhibitory effects on macrophages. We also hypothesized that the antifibrotic effect of NRG-1 may be active in other organs, such as the skin and lung. First, in a mouse model of angiotensin II (ANG II)-induced myocardial hypertrophy and fibrosis, NRG-1 treatment (20 µg·kg-1·day-1 ip) significantly attenuated myocardial hypertrophy and fibrosis and improved passive ventricular stiffness (4 wk). Interestingly, 1 wk after exposure to ANG II, NRG-1 already attenuated myocardial macrophage infiltration and cytokine expression. Furthermore, mice with myeloid-specific deletion of the ErbB4 gene (ErbB4F/FLysM-Cre+/-) showed an intensified myocardial fibrotic response to ANG II. Consistently, NRG-1 activated the ErbB4 receptor in isolated macrophages, inhibited phosphatidylinositide 3-kinase/Akt and STAT3 signaling pathways, and reduced the release of inflammatory cytokines. Further experiments showed that the antifibrotic and anti-inflammatory effects of NRG-1 were reproducible in mouse models of bleomycin-induced dermal and pulmonary fibrosis. Overall, this study demonstrates that the antifibrotic effect of NRG-1 in the heart is linked to anti-inflammatory activity NRG-1/ErbB4 signaling in macrophages. Second, this study shows that NRG-1 has antifibrotic and anti-inflammatory effects in organs other than the heart, such as the skin and lung.NEW & NOTEWORTHY Our study contributes to the understanding of the antifibrotic effect of neuregulin-1 during myocardial remodeling. Here, we show that the antifibrotic effect of neuregulin-1 is at least partially mediated through anti-inflammatory activity, linked to receptor tyrosine-protein kinase erbB-4 activation in macrophages. Furthermore, we show that this effect is also present outside the heart.
Assuntos
Macrófagos/metabolismo , Miocárdio/patologia , Neuregulina-1/metabolismo , Fibrose Pulmonar/patologia , Receptor ErbB-4/metabolismo , Transdução de Sinais , Pele/patologia , Animais , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Ecocardiografia , Fibrose , Coração/diagnóstico por imagem , Hemodinâmica , Camundongos , Camundongos Endogâmicos C57BL , Miocardite/patologia , Miócitos Cardíacos/patologia , Fibrose Pulmonar/diagnóstico por imagem , Pele/diagnóstico por imagemRESUMO
KEY POINTS: Cyclic stretch is known to alter intracellular pathways involved in vessel tone regulation. We developed a novel set-up that allows straightforward characterization of the biomechanical properties of the mouse aorta while stretched at a physiological heart rate (600 beats min-1 ). Active vessel tone was shown to have surprisingly large effects on isobaric stiffness. The effect of structural vessel wall alterations was confirmed using a genetic mouse model. This set-up will contribute to a better understanding of how active vessel wall components and mechanical stimuli such as stretch frequency and amplitude regulate aortic mechanics. ABSTRACT: Cyclic stretch is a major contributor to vascular function. However, isolated mouse aortas are frequently studied at low stretch frequency or even in isometric conditions. Pacing experiments in rodents and humans show that arterial compliance is stretch frequency dependent. The Rodent Oscillatory Tension Set-up to study Arterial Compliance is an in-house developed organ bath set-up that clamps aortic segments to imposed preloads at physiological rates up to 600 beats min-1 . The technique enables us to derive pressure-diameter loops and assess biomechanical properties of the segment. To validate the applicability of this set-up we aimed to confirm the effects of distension pressure and vascular smooth muscle tone on arterial stiffness. At physiological stretch frequency (10 Hz), the Peterson modulus (EP ; 293 (10) mmHg) for wild-type mouse aorta increased 22% upon a rise in pressure from 80-120 mmHg to 100-140 mmHg, while, at normal pressure, EP increased 80% upon maximal contraction of the vascular smooth muscle cells. We further validated the method using a mouse model with a mutation in the fibrillin-1 gene and an endothelial nitric oxide synthase knock-out model. Both models are known to have increased arterial stiffness, and this was confirmed using the set-up. To our knowledge, this is the first set-up that facilitates the study of biomechanical properties of mouse aortic segments at physiological stretch frequency and pressure. We believe that this set-up can contribute to a better understanding of how cyclic stretch frequency, amplitude and active vessel wall components influence arterial stiffening.
Assuntos
Aorta/fisiologia , Contração Muscular , Técnicas de Cultura de Órgãos/métodos , Amplificadores Eletrônicos , Animais , Fenômenos Biomecânicos , Camundongos , Camundongos Endogâmicos C57BL , Miografia/instrumentação , Miografia/métodos , Técnicas de Cultura de Órgãos/instrumentaçãoRESUMO
Arterial hypertension (AHT) affects the voltage dependency of L-type Ca(2+) channels in cardiomyocytes. We analyzed the effect of angiotensin II (AngII)-induced AHT on L-type Ca(2+) channel-mediated isometric contractions in conduit arteries. AHT was induced in C57Bl6 mice with AngII-filled osmotic mini-pumps (4 weeks). Normotensive mice treated with saline-filled osmotic mini-pumps were used for comparison. Voltage-dependent contractions mediated by L-type Ca(2+) channels were studied in vaso-reactive studies in vitro in isolated aortic and femoral arteries by using extracellular K(+) concentration-response (KDR) experiments. In aortic segments, AngII-induced AHT significantly sensitized isometric contractions induced by elevated extracellular K(+) and depolarization. This sensitization was partly prevented by normalizing blood pressure with hydralazine, suggesting that it was caused by AHT rather than by direct AngII effects on aortic smooth muscle cells. The EC50 for extracellular K(+) obtained in vitro correlated significantly with the rise in arterial blood pressure induced by AngII in vivo. The AHT-induced sensitization persisted when aortic segments were exposed to levcromakalim or to inhibitors of basal nitric oxide release. Consistent with these observations, AngII-treatment also sensitized the vaso-relaxing effects of the L-type Ca(2+) channel blocker diltiazem during K(+)-induced contractions. Unlike aorta, AngII-treatment desensitized the isometric contractions to depolarization in femoral arteries pointing to vascular bed specific responses of arteries to hypertension. AHT affects the voltage-dependent L-type Ca(2+) channel-mediated contraction of conduit arteries. This effect may contribute to the decreased vascular compliance in AHT and explain the efficacy of Ca(2+) channel blockers to reduce vascular stiffness and central blood pressure in AHT.
Assuntos
Angiotensina II/metabolismo , Artérias/fisiologia , Canais de Cálcio Tipo L/metabolismo , Hipertensão/metabolismo , Contração Muscular , Vasodilatação , Potenciais de Ação , Angiotensina II/efeitos dos fármacos , Animais , Artérias/efeitos dos fármacos , Artérias/metabolismo , Pressão Sanguínea , Bloqueadores dos Canais de Cálcio/farmacologia , Cromakalim/farmacologia , Diltiazem/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiologia , Óxido Nítrico/metabolismo , Potássio/metabolismo , Potássio/farmacologiaRESUMO
Neuregulin-1 (NRG-1) is an endothelium-derived growth factor with cardioprotective and antiatherosclerotic properties and is currently being tested in clinical trials as a treatment for systolic heart failure. In clinical practice, heart failure often coexists with renal failure, sharing an overlapping pathophysiological background. In this study, we hypothesized that NRG-1 might protect against cardiomyopathy, atherosclerosis, and nephropathy within one disease process. We tested this hypothesis in a hypercholesterolemic apolipoprotein E-deficient (apoE(-/-)) type 1 diabetes mouse model prone to the development of cardiomyopathy, atherosclerosis, and nephropathy and compared the effects of NRG-1 with insulin. Upon onset of hyperglycemia induced by streptozotocin, apoE(-/-)mice were treated with vehicle, insulin, or recombinant human (rh)NRG-1 for 14 wk and were compared with nondiabetic apoE(-/-)littermates. Vehicle-treated diabetic apoE(-/-)mice developed left ventricular (LV) dilatation and dysfunction, dense atherosclerotic plaques, and signs of nephropathy. Nephropathy was characterized by abnormalities including hyperfiltration, albuminuria, increased urinary neutrophil gelatinase-associated lipocalin (NGAL), upregulation of renal fibrotic markers, and glomerulosclerosis. rhNRG-1 treatment induced systemic activation of ErbB2 and ErbB4 receptors in both heart and kidneys and prevented LV dilatation, improved LV contractile function, and reduced atherosclerotic plaque size. rhNRG-1 also significantly reduced albuminuria, NGALuria, glomerular fibrosis, and expression of fibrotic markers. Regarding the renal effects of rhNRG-1, further analysis showed that rhNRG-1 inhibited collagen synthesis of glomerular mesangial cells in vitro but did not affect AngII-induced vasoconstriction of glomerular arterioles. In conclusion, systemic administration of rhNRG-1 in hypercholesterolemic type 1 diabetic mice simultaneously protects against complications in the heart, arteries and kidneys.
Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Nefropatias Diabéticas/patologia , Coração/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Rim/efeitos dos fármacos , Neuregulina-1/farmacologia , Placa Aterosclerótica/patologia , Animais , Apolipoproteínas E/genética , Arteríolas/efeitos dos fármacos , Doenças Cardiovasculares , Colágeno/biossíntese , Colágeno/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/fisiopatologia , Modelos Animais de Doenças , Ventrículos do Coração/efeitos dos fármacos , Hipercolesterolemia/complicações , Hipercolesterolemia/genética , Glomérulos Renais/efeitos dos fármacos , Células Mesangiais/efeitos dos fármacos , Camundongos , Camundongos Knockout , Contração Miocárdica/efeitos dos fármacos , Receptor ErbB-2/efeitos dos fármacos , Receptor ErbB-4/efeitos dos fármacos , Proteínas Recombinantes , Risco , Vasoconstrição/efeitos dos fármacosRESUMO
The dual role of ErbB2 (or HER-2) in tumor growth and in physiological adaptive reactions of the heart positions ErbB2 at the intersection between cancer and chronic heart failure. Accordingly, ErbB2-targeted inhibitory therapy of cancer may lead to ventricular dysfunction, and activation of ErbB2 for heart failure therapy may induce malignancy. The molecular processes leading to the activation of ErbB2 in tumors and cardiac cells are, however, fundamentally different from each other. Thus, it must be feasible to design drugs that specifically target either physiological or malignant ErbB2 signaling, to activate ErbB2 signaling in heart failure with no increased risk for cancer, and to inhibit ErbB2 signaling in cancer with no increased risk for heart failure. In this review, we present a state-of-the-art on how ErbB2 is regulated in physiological conditions and in tumor cells and how this knowledge translates into smart drug design. This leads to a new generation of drugs interfering with ErbB2 in a unique way tailored for a specific clinical goal. These exciting developments at the crossing between cancer and heart failure are an elegant example of interdisciplinary collaborations between clinicians, physiologists, pharmacologists, and molecular biologists.
Assuntos
Insuficiência Cardíaca/metabolismo , Neoplasias/metabolismo , Receptor ErbB-2/metabolismo , Transdução de Sinais/fisiologia , Animais , Insuficiência Cardíaca/fisiopatologia , Humanos , Neoplasias/fisiopatologiaRESUMO
Heart failure (HF) is an important global health problem with great socioeconomic burden. Outcomes remain sub-optimal. Endothelium-cardiomyocyte interactions play essential roles in cardiovascular homeostasis, and deranged endothelium-related signalling pathways have been implicated in the pathophysiology of HF. In particular, disturbances in nitric oxide (NO)-mediated pathway and neuregulin-mediated pathway have been shown to contribute to the development of HF. These signalling pathways hold the potential as pathophysiological targets for new HF therapies, and may aid in patient selection for future HF trials.
RESUMO
AIMS: There is a need for animal models of plaque rupture. We previously reported that elastin fragmentation, due to a mutation (C1039G(+/-)) in the fibrillin-1 (Fbn1) gene, promotes atherogenesis and a highly unstable plaque phenotype in apolipoprotein E deficient (ApoE(-/-)) mice on a Western-type diet (WD). Here, we investigated whether plaque rupture occurred in ApoE(-/-)Fbn1(C1039G+/-) mice and was associated with myocardial infarction, stroke, and sudden death. METHODS AND RESULTS: Female ApoE(-/-)Fbn1(C1039G+/-) and ApoE(-/-) mice were fed a WD for up to 35 weeks. Compared to ApoE(-/-) mice, plaques of ApoE(-/-)Fbn1(C1039G+/-) mice showed a threefold increase in necrotic core size, augmented T-cell infiltration, a decreased collagen I content (70 ± 10%), extensive neovascularization, intraplaque haemorrhage, and a significant increase in matrix metalloproteinase-2, -9, -12, and -13 expression or activity. Plaque rupture was observed in 70% of ascending aortas and in 50% of brachiocephalic arteries of ApoE(-/-)Fbn1(C1039G+/-) mice. In ApoE(-/-) mice, plaque rupture was not seen in ascending aortas and only in 10% of brachiocephalic arteries. Seventy percent of ApoE(-/-)Fbn1(C1039G+/-) mice died suddenly, whereas all ApoE(-/-) mice survived. ApoE(-/-)Fbn1(C1039G+/-) mice showed coronary plaques and myocardial infarction (75% of mice). Furthermore, they displayed head tilt, disorientation, and motor disturbances (66% of cases), disturbed cerebral blood flow (73% of cases; MR angiograms) and brain hypoxia (64% of cases), indicative of stroke. CONCLUSIONS: Elastin fragmentation plays a key role in plaque destabilization and rupture. ApoE(-/-)Fbn1(C1039G+/-) mice represent a unique model of acute plaque rupture with human-like complications.