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BACKGROUND & AIMS: Visceral smooth muscle cells (SMCs) are an integral component of the gastrointestinal (GI) tract that regulate GI motility. SMC contraction is regulated by posttranslational signaling and the state of differentiation. Impaired SMC contraction is associated with significant morbidity and mortality, but the mechanisms regulating SMC-specific contractile gene expression, including the role of long noncoding RNAs (lncRNAs), remain largely unexplored. Herein, we reveal a critical role of Carmn (cardiac mesoderm enhancer-associated noncoding RNA), an SMC-specific lncRNA, in regulating visceral SMC phenotype and contractility of the GI tract. METHODS: Genotype-Tissue Expression and publicly available single-cell RNA sequencing (scRNA-seq) data sets from embryonic, adult human, and mouse GI tissues were interrogated to identify SMC-specific lncRNAs. The functional role of Carmn was investigated using novel green fluorescent protein (GFP) knock-in (KI) reporter/knock-out (KO) mice. Bulk RNA-seq and single nucleus RNA sequencing (snRNA-seq) of colonic muscularis were used to investigate underlying mechanisms. RESULTS: Unbiased in silico analyses and GFP expression patterns in Carmn GFP KI mice revealed that Carmn is highly expressed in GI SMCs in humans and mice. Premature lethality was observed in global Carmn KO and inducible SMC-specific KO mice due to GI pseudo-obstruction and severe distension of the GI tract, with dysmotility in cecum and colon segments. Histology, GI transit, and muscle myography analysis revealed severe dilation, significantly delayed GI transit, and impaired GI contractility in Carmn KO vs control mice. Bulk RNA-seq of GI muscularis revealed that loss of Carmn promotes SMC phenotypic switching, as evidenced by up-regulation of extracellular matrix genes and down-regulation of SMC contractile genes, including Mylk, a key regulator of SMC contraction. snRNA-seq further revealed SMC Carmn KO not only compromised myogenic motility by reducing contractile gene expression but also impaired neurogenic motility by disrupting cell-cell connectivity in the colonic muscularis. These findings may have translational significance, because silencing CARMN in human colonic SMCs significantly attenuated contractile gene expression, including MYLK, and decreased SMC contractility. Luciferase reporter assays showed that CARMN enhances the transactivation activity of the master regulator of SMC contractile phenotype, myocardin, thereby maintaining the GI SMC myogenic program. CONCLUSIONS: Our data suggest that Carmn is indispensable for maintaining GI SMC contractile function in mice and that loss of function of CARMN may contribute to human visceral myopathy. To our knowledge this is the first study showing an essential role of lncRNA in the regulation of visceral SMC phenotype.
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Contração Muscular , Músculo Liso , RNA Longo não Codificante , Animais , Humanos , Camundongos , Diferenciação Celular , Células Cultivadas , Camundongos Knockout , Miócitos de Músculo Liso/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismoRESUMO
BACKGROUND: Mendelian randomization analysis was applied to elucidate the causal relationship between the basal metabolic rate (BMR) and common cardiovascular diseases. METHOD: We choose BMR as exposure. BMR is the metabolic rate of the body when the basic physiological activities (blood circulation, breathing and constant body temperature) are maintained. The normal BMR is 1507 kcal/day for men and 1276 kcal/day for women. The dataset was drawn from the public GWAS dataset (GWAS ID: ukb-a-268), collected and analysed by UK biobank, containing 331,307 European males and females. SNPs independently and strongly associated with BMR were used as instrumental variables in the inverse variance weighted analysis. MR-Egger, weighted median, MR pleiotropy residual sum, and outlier methods were also performed, and the sensitivity was evaluated using horizontal pleiotropy and heterogeneity analyses to ensure the stability of the results. RESULTS: An increased BMR is associated with a higher risk of cardiomyopathy (odds ratio [OR] = 2.00, 95% confidence interval [CI], 1.57-2.54, p = 1.87 × 10-8), heart failure (OR = 1.39, 95% CI, 1.27-2.51, p = 8.1 × 10-13), and valvular heart disease (OR = 1.18, 95% CI, 1.10-1.27, p = .00001). However, there was no clear association between BMR and the subtypes of other cardiovascular diseases, such as coronary disease (OR = .96, 95% CI, .85-1.08, p = .48651) and atrial fibrillation (AF) (OR = 1.85, 95% CI, 1.70-2.02, p = 6.28 × 10-44). CONCLUSION: Our study reveals a possible causal effect of BMR on the risk of cardiomyopathy, heart failure and valvular disease, but not for coronary disease and AF.
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Fibrilação Atrial , Cardiomiopatias , Doenças Cardiovasculares , Doença da Artéria Coronariana , Insuficiência Cardíaca , Masculino , Feminino , Humanos , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Metabolismo Basal , Análise da Randomização MendelianaRESUMO
BACKGROUND: Angiogenesis is a promising strategy for those with peripheral artery disease. Macrophage-centered inflammation is intended to govern the deficiency of the angiogenic response after hindlimb ischemia. However, little is known about the mechanism of macrophage activation beyond signals from cytokines and chemokines. We sought to identify a novel mechanical signal from the ischemic microenvironment that provokes macrophages and the subsequent inflammatory cascade and to investigate the potential role of Piezo-type mechanosensitive ion channels (Piezo) on macrophages during this process. METHODS: Myeloid cell-specific Piezo1 (Piezo-type mechanosensitive ion channel component 1) knockout (Piezo1ΔMΦ) mice were generated by crossing Piezo1fl/fl (LysM-Cre-/-; Piezo1 flox/flox) mice with LysM-Cre transgenic mice to assess the roles of Piezo1 in macrophages after hindlimb ischemia. Furthermore, in vitro studies were carried out in bone marrow-derived macrophages to decipher the underlying mechanism. RESULTS: We found that tissue stiffness gradually increased after hindlimb ischemia, as indicated by Young's modulus. Compared to Piezo2, Piezo1 expression and activation were markedly upregulated in macrophages from ischemic tissues in concurrence with increased tissue stiffness. Piezo1ΔMΦ mice exhibited improved perfusion recovery by enhancing angiogenesis. Matrigel tube formation assays revealed that Piezo1 deletion promoted angiogenesis by enhancing FGF2 (fibroblast growth factor-2) paracrine signaling in macrophages. Conversely, activation of Piezo1 by increased stiffness or the agonist Yoda1 led to reduced FGF2 production in bone marrow-derived macrophages, which could be blocked by Piezo1 silencing. Mechanistically, Piezo1 mediated extracellular Ca2+ influx and activated Ca2+-dependent CaMKII (calcium/calmodulin-dependent protein kinase II)/ETS1 (ETS proto-oncogene 1) signaling, leading to transcriptional inactivation of FGF2. CONCLUSIONS: This study uncovers a crucial role of microenvironmental stiffness in exacerbating the macrophage-dependent deficient angiogenic response. Deletion of macrophage Piezo1 promotes perfusion recovery after hindlimb ischemia through CaMKII/ETS1-mediated transcriptional activation of FGF2. This provides a promising therapeutic strategy to enhance angiogenesis in ischemic diseases.
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Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Fator 2 de Crescimento de Fibroblastos , Animais , Camundongos , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Canais Iônicos , Camundongos Transgênicos , Macrófagos/metabolismo , Isquemia , Perfusão , Membro Posterior/irrigação sanguíneaRESUMO
Sepsis is a major cause of mortality in intensive care units, which results from a severely dysregulated inflammatory response that ultimately leads to organ failure. While antibiotics can help in the early stages, effective strategies to curtail inflammation remain limited. The high mobility group (HMG) proteins are chromosomal proteins with important roles in regulating gene transcription. While HMGB1 has been shown to play a role in sepsis, the role of other family members including HMGXB4 remains unknown. We found that expression of HMGXB4 is strongly induced in response to lipopolysaccharide (LPS)-elicited inflammation in murine peritoneal macrophages. Genetic deletion of Hmgxb4 protected against LPS-induced lung injury and lethality and cecal ligation and puncture (CLP)-induced lethality in mice, and attenuated LPS-induced proinflammatory gene expression in cultured macrophages. By integrating genome-wide transcriptome profiling and a publicly available ChIP-seq dataset, we identified HMGXB4 as a transcriptional activator that regulates the expression of the proinflammatory gene, Nos2 (inducible nitric oxide synthase 2) by binding to its promoter region, leading to NOS2 induction and excessive NO production and tissue damage. Similar to Hmgxb4 ablation in mice, administration of a pharmacological inhibitor of NOS2 robustly decreased LPS-induced pulmonary vascular permeability and lethality in mice. Additionally, we identified the cell adhesion molecule, ICAM1, as a target of HMGXB4 in endothelial cells that facilitates inflammation by promoting monocyte attachment. In summary, our study reveals a critical role of HMGXB4 in exacerbating endotoxemia via transcriptional induction of Nos2 and Icam1 gene expression and thus targeting HMGXB4 may be an effective therapeutic strategy for the treatment of sepsis.
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Endotoxemia/metabolismo , Animais , Células Endoteliais/metabolismo , Endotoxemia/etiologia , Endotoxemia/genética , Feminino , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Lipopolissacarídeos/toxicidade , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , TranscriptomaRESUMO
Cardiac calcification is a crucial but underrecognized pathological process, greatly increasing the risk of cardiovascular diseases. Little is known about how cardiac fibroblasts, as a central mediator, facilitate abnormal mineralization. Erythropoietin-producing hepatoma interactor B2 (EphrinB2), previously identified as an angiogenic regulator, is involved in fibroblast activation, while its role in the osteogenic differentiation of cardiac fibroblasts is unknown. Bioinformatics analysis was conducted to characterize the expression of the Ephrin family in human calcified aortic valves and calcific mouse hearts. The effects of EphrinB2 on cardiac fibroblasts to adopt osteogenic fate was determined by gain- and loss-of-function. EphrinB2 mRNA level was downregulated in calcified aortic valves and mouse hearts. Knockdown of EphrinB2 attenuated mineral deposits in adult cardiac fibroblasts, whereas overexpression of EphrinB2 promoted their osteogenic differentiation. RNA sequencing data implied that Ca2+-related S100/receptor for advanced glycation end products (RAGE) signaling may mediate EphrinB2-induced mineralization in cardiac fibroblasts. Moreover, L-type calcium channel blockers inhibited osteogenic differentiation of cardiac fibroblasts, implying a critical role in Ca2+ influx. In conclusion, our data illustrated an unrecognized role of EphrinB2, which functions as a novel osteogenic regulator in the heart through Ca2+ signaling and could be a potential therapeutic target in cardiovascular calcification.NEW & NOTEWORTHY In this study, we observed that adult cardiac fibroblasts but not neonatal cardiac fibroblasts exhibit the ability of osteogenic differentiation. EphrinB2 promoted osteogenic differentiation of cardiac fibroblasts through activating Ca2+-related S100/RAGE signaling. Inhibition of Ca2+ influx using L-type calcium channel blockers inhibited EphrinB2-mediated calcification of cardiac fibroblasts. Our data implied an unrecognized role of EphrinB2 in regulating cardiac calcification though Ca2+-related signaling, suggesting a potential therapeutic target of cardiovascular calcification.
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Carcinoma Hepatocelular , Eritropoetina , Neoplasias Hepáticas , Adulto , Animais , Humanos , Camundongos , Cálcio , Bloqueadores dos Canais de Cálcio/farmacologia , Diferenciação Celular , Eritropoetina/farmacologia , Fibroblastos , Osteogênese/fisiologia , Receptor para Produtos Finais de Glicação AvançadaRESUMO
Background: The Serum creatinine/cystatin C ratio (Cr/CysC ratio) is an emerging alternative index for muscle mass loss, a risk factor for cardiovascular diseases (CVDs). However, the association between the Cr/CysC ratio and CVD morbidity and mortality remains unknown. Methods: A total of 11,150 participants of the National Health and Nutrition Examination Survey (NHANES) were included in this study. Univariable and multivariable logistic regression models were employed to assess the association between the Cr/CysC ratio and self-reported CVD morbidity. Cox proportional hazard models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) of the Cr/CysC ratio for CVD mortality. Results: At baseline, 1181 (7.90%) participants had self-reported CVDs. Lower Cr/CysC ratios were found in participants with CVDs (1.18 ± 0.30 vs. 1.05 ± 0.23, p < 0.001). In the multivariable logistic regression model, the Cr/CysC ratio was inversely linked to CVD morbidity (odds ratio: 0.65, 95% CI: 0.52-0.81, p < 0.001, per standard deviation [SD] increase). 997 (8.94%) CVD deaths were documented during a median follow-up of 16.9 years. A higher Cr/CysC ratio was associated with a decreasing risk of CVD mortality (adjusted HR: 0.54, 95% CI: 0.46-0.65, p < 0.001, per SD increase). Conclusions: In NHANES participants, the Cr/CysC ratio had an inverse correlation with CVD morbidity and mortality.
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Background: Mitral regurgitation (MR) has a high prevalence and aggravates hypoperfusion and hypoxia in heart failure (HF). Renal tubular epithelial cells are sensitive to hypoxia, and therefore tubulointerstitial damage is quite common in HF. However, the correlation between tubular dysfunction and MR has not been studied. The aim of this work was to evaluate the prognostic significance of urinary N-acetyl- ß -d-glucosaminidase (uNAG), a biomarker of renal tubular damage, in patients with HF and MR. Methods: This was a prospective cohort study of 390 patients (mean age 64 years; 65.6% male) with uNAG measurement on admission (expressed as urinary NAG/urinary creatinine) and at least 1 year of follow-up data. The pre-defined primary endpoint was the composite of all-cause mortality or rehospitalization for HF after discharge. Cox regression analysis, restricted cubic splines, and subgroup analysis were used to investigate the prognostic value of uNAG modeled as a categorical (quartiles) or continuous (per SD increase) variable. Results: A total of 153 (39.23%) patients reached the composite endpoint over a median follow-up time of 1.2 years. The uNAG level correlated with the severity of HF and with the incidence of adverse events. In a multivariable Cox regression model, each SD (13.80 U/g â Cr) of increased uNAG was associated with a 17% higher risk of death or HF rehospitalization (95% confidence interval, 2-33%, p = 0.022), and a 19% higher risk of HF rehospitalization (p = 0.027). Subgroup analysis revealed the associations between uNAG and poor prognosis were only significant in younger patients ( ≤ 65 years) and in patients without obvious cardiovascular comorbidities. Conclusions: uNAG levels at admission were associated with the risk of adverse outcomes in patients with HF and MR. Additional studies are needed to further investigate the heart-kidney interaction.
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OBJECTIVES: To evaluate at 1.5 and 3 T MRI the safety and performance of trademarked ENO®, TEO®, or OTO® pacing systems with automated MRI Mode and the image quality of non-enhanced MR examinations. METHODS: A total of 267 implanted patients underwent MRI examination (brain, cardiac, shoulder, cervical spine) at 1.5 (n = 126) or 3 T (n = 141). MRI-related device complications, lead electrical performances stability at 1-month post-MRI, proper functioning of the automated MRI mode and image quality were evaluated. RESULTS: Freedom from MRI-related complications at 1 month post-MRI was 100% in both 1.5 and 3 T arms (both p < 0.0001). The stability of pacing capture threshold was respectively at 1.5 and 3 T (atrial:: 98.9% (p = 0.001) and 100% (p < 0.0001); ventricular: both 100% (p < 0001)). The stability of sensing was respectively at 1.5 and 3 T (atrial: 100% (p = 0.0001) and 96.9% (p = 0.01); ventricular: 100% (p < 0.0001) and 99.1% (p = 0.0001)). All devices switched automatically to the programmed asynchronous mode in the MRI environment and to initially programmed mode after the MRI exam. While all MR examinations were assessed as interpretable, artifacts deteriorated a subset of examinations including mostly cardiac and shoulder ones. CONCLUSION: This study demonstrates the safety and electrical stability of ENO®, TEO®, or OTO® pacing systems at 1 month post-MRI at 1.5 and 3 T. Even if artifacts were noticed in a subset of examinations, overall interpretability was preserved. CLINICAL RELEVANCE STATEMENT: ENO®, TEO®, and OTO® pacing systems switch to MR-mode when detecting magnetic field and switch back on conventional mode after MRI. Their safety and electrical stability at 1 month post MRI were shown at 1.5 and 3 T. Overall interpretability was preserved. KEY POINTS: ⢠Patients implanted with an MRI conditional cardiac pacemaker can be safely scanned under 1.5 or 3 Tesla MRI with preserved interpretability. ⢠Electrical parameters of the MRI conditional pacing system remain stable after a 1.5 or 3 Tesla MRI scan. ⢠The automated MRI mode enabled the automatic switch to asynchronous mode in the MRI environment and to initial settings after the MRI scan in all patients.
Assuntos
Fibrilação Atrial , Marca-Passo Artificial , Humanos , Segurança de Equipamentos/métodos , Estudos Prospectivos , Imageamento por Ressonância Magnética/métodosRESUMO
BACKGROUND: Vascular homeostasis is maintained by the differentiated phenotype of vascular smooth muscle cells (VSMCs). The landscape of protein coding genes comprising the transcriptome of differentiated VSMCs has been intensively investigated but many gaps remain including the emerging roles of noncoding genes. METHODS: We reanalyzed large-scale, publicly available bulk and single-cell RNA sequencing datasets from multiple tissues and cell types to identify VSMC-enriched long noncoding RNAs. The in vivo expression pattern of a novel smooth muscle cell (SMC)-expressed long noncoding RNA, Carmn (cardiac mesoderm enhancer-associated noncoding RNA), was investigated using a novel Carmn green fluorescent protein knock-in reporter mouse model. Bioinformatics and quantitative real-time polymerase chain reaction analysis were used to assess CARMN expression changes during VSMC phenotypic modulation in human and murine vascular disease models. In vitro, functional assays were performed by knocking down CARMN with antisense oligonucleotides and overexpressing Carmn by adenovirus in human coronary artery SMCs. Carotid artery injury was performed in SMC-specific Carmn knockout mice to assess neointima formation and the therapeutic potential of reversing CARMN loss was tested in a rat carotid artery balloon injury model. The molecular mechanisms underlying CARMN function were investigated using RNA pull-down, RNA immunoprecipitation, and luciferase reporter assays. RESULTS: We identified CARMN, which was initially annotated as the host gene of the MIR143/145 cluster and recently reported to play a role in cardiac differentiation, as a highly abundant and conserved, SMC-specific long noncoding RNA. Analysis of the Carmn GFP knock-in mouse model confirmed that Carmn is transiently expressed in embryonic cardiomyocytes and thereafter becomes restricted to SMCs. We also found that Carmn is transcribed independently of Mir143/145. CARMN expression is dramatically decreased by vascular disease in humans and murine models and regulates the contractile phenotype of VSMCs in vitro. In vivo, SMC-specific deletion of Carmn significantly exacerbated, whereas overexpression of Carmn markedly attenuated, injury-induced neointima formation in mouse and rat, respectively. Mechanistically, we found that Carmn physically binds to the key transcriptional cofactor myocardin, facilitating its activity and thereby maintaining the contractile phenotype of VSMCs. CONCLUSIONS: CARMN is an evolutionarily conserved SMC-specific long noncoding RNA with a previously unappreciated role in maintaining the contractile phenotype of VSMCs and is the first noncoding RNA discovered to interact with myocardin.
Assuntos
Contração Muscular , Músculo Liso Vascular/metabolismo , Músculo Liso/metabolismo , Proteínas Nucleares/metabolismo , RNA Longo não Codificante/metabolismo , Transativadores/metabolismo , Animais , Humanos , Camundongos , Proteínas Nucleares/genética , RNA Longo não Codificante/genética , Ratos , Transativadores/genéticaRESUMO
Background: Mitral regurgitation (MR) is one of the common complications of heart failure (HF). The prevalence and characteristics of MR are rarely investigated, especially in the Chinese population. Objectives: The purpose of this study was to determine the prevalence and characteristics of non-organic MR in HF patients and subgroups defined by ejection fraction. Methods: A single-center, hospital-based, and retrospective chart review study included patients with heart failure admitted to the cardiovascular department from January 2017 to April 2020. Demographic characteristics, laboratory results, and echocardiogram results before discharge were analyzed in different groups defined by left ventricular ejection fraction (EF) using logistic regression and adjusted for confounders. Results: Finally, 2418 validated HF patients (age 67.2 ± 13.5 years; 68.03% men) were included. The prevalence of MR was 32.7% in HF, 16.7% in HF with preserve EF patients, 28.4% in HF with mid-range EF patients and 49.7% in HF with reduced EF (HFrEF) patients. In the HF with preserved EF group, multivariable logistic regression showed that 4 factors associated with MR including EF (odds ratio (OR) 0.954 (0.928-0.981), p = 0.001), left ventricular posterior wall thickness in diastolic phase (LVPWd) (OR 0.274 (0.081-0.932), p = 0.038), left atrium (LA) dimension (OR 2.049 (1.631-2.576), p < 0.001) and age (OR 1.024 (1.007-1.041), p = 0.007). In the HF with midrange EF group, multivariable logistic regression showed that 3 factors associated with MR including LA dimension (OR 2.009 (1.427-2.829), p < 0.001), triglycerides (TG) (OR 0.552 (0.359-0.849), p = 0.007) and digoxin (OR 2.836 (1.624-4.951), p < 0.001). In the HFrEF group, multivariable logistic regression showed that 7 factors associated with MR including EF (OR 0.969 (0.949-0.990), p = 0.004), (OR 0.161 (0.067-0.387), p < 0.001), LA dimension (OR 2.289 (1.821-2.878), p < 0.001), age (OR 1.016 (1.004-1.027)), p = 0.009), TG (OR 0.746 (0.595-0.936), p = 0.011), diuretics (OR 0.559 (0.334-0.934), p = 0.026) and ICD (OR 1.898 (1.074-3.354), p = 0.027). Conclusions: HF patients had a high burden of MR, particularly in the HFrEF group. Worsen cardiac structure (LA dimension and LVPWd) and function (EF), age, and medical treatment strategy played essential roles in MR.
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[Figure: see text].
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Heme Oxigenase-1/metabolismo , Inflamassomos/metabolismo , Isquemia/enzimologia , Lisossomos/enzimologia , Macrófagos/enzimologia , Proteínas de Membrana/metabolismo , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/enzimologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Células Cultivadas , Bases de Dados Genéticas , Modelos Animais de Doenças , Heme Oxigenase-1/genética , Membro Posterior , Humanos , Inflamassomos/genética , Mediadores da Inflamação/metabolismo , Isquemia/genética , Isquemia/fisiopatologia , Masculino , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Esquelético/fisiopatologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Neovascularização Fisiológica , Proteólise , Recuperação de Função Fisiológica , Fluxo Sanguíneo RegionalRESUMO
Cardiovascular calcification, a kind of ectopic mineralization in cardiovascular system, including atherosclerotic calcification, arterial medial calcification, valve calcification and the gradually recognized heart muscle calcification, is a complex pathophysiological process correlated with poor prognosis. Although several cell types such as smooth muscle cells have been proven critical in vascular calcification, the aetiology of cardiovascular calcification remains to be clarified due to the diversity of cellular origin. Fibroblasts, which possess remarkable phenotypic plasticity that allows rapid adaption to fluctuating environment cues, have been demonstrated to play important roles in calcification of vasculature, valve and heart though our knowledge of the mechanisms controlling fibroblast phenotypic switching in the calcified process is far from complete. Indeed, the lack of definitive fibroblast lineage-tracing studies and typical expression markers of fibroblasts raise major concerns regarding the contributions of fibroblasts during all the stages of cardiovascular calcification. The goal of this review was to rigorously summarize the current knowledge regarding possible phenotypes exhibited by fibroblasts within calcified cardiovascular system and evaluate the potential therapeutic targets that may control the phenotypic transition of fibroblasts in cardiovascular calcification.
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Calcinose/etiologia , Calcinose/metabolismo , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Fibroblastos/metabolismo , Animais , Biomarcadores , Calcinose/patologia , Doenças Cardiovasculares/patologia , Suscetibilidade a Doenças , Humanos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Transdução de Sinais , Calcificação Vascular/etiologia , Calcificação Vascular/metabolismo , Calcificação Vascular/patologiaRESUMO
Trimetazidine has been reported to benefit patients with heart failure (HF) and angina. The impact of trimetazidine on non-ischemic HF remains unclear. We reviewed clinical trials to investigate whether trimetazidine could improve exercise endurance, life quality, and heart function in non-ischemic HF patients. We searched the Cochrane Central Register of Controlled Trials, EMBASE, PubMed, and Web of science for randomized clinical trials published before April 30th, 2020; Studies limited to patients with non-ischemic HF, aged ≥18 years, comparing trimetazidine with conventional therapy with/without placebo. Outcome measurements included primary outcomes (6 minutes walking test (6-MWT)) and secondary outcomes (life quality scores, echocardiography parameters, biomarker, peak oxygen consumption). The follow-up period was longer than three months. This study was registered with international prospective register of systematic reviews (PROSPERO) (CRD42020182982). Six studies with 310 cases were included in this research. Trimetazidine significantly improved 6-MWT (weighted mean difference (WMD) = 48.51 m, 95% confidence interval (CI) [29.41, 67.61], p < 0.0001, I2 = 0%), left ventricle ejection fraction (LVEF) (WMD = 3.09%, 95% CI [1.09, 5.01], p = 0.002, I2 = 0%) at 3 months, and LVEF (WMD = 6.09%, 95% CI [3.76, 8.42], p < 0.0001, I2 = 12%) at 6 months. Furthermore, it reduced peak oxygen consumption (WMD = -2.24 mL/kg per minute, 95% CI [-4.09, -0.93], p = 0.02). This meta-analysis suggested that trimetazidine might be an effective strategy for improving exercise endurance and cardiac function in patients with non-ischemic HF.
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Insuficiência Cardíaca , Trimetazidina , Adolescente , Adulto , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Trimetazidina/efeitos adversos , Vasodilatadores/efeitos adversosRESUMO
Cathepsin B (CatB) is a cysteine proteolytic enzyme widely expressed in various cells and mainly located in the lysosomes. It contributes to the pathogenesis and development of many diseases. However, the role of CatB in viral myocarditis (VMC) has never been elucidated. Here we generated the VMC model by intraperitoneal injection of coxsackievirus B3 (CVB3) into mice. At day 7 and day 28, we found CatB was significantly activated in hearts from VMC mice. Compared with the wild-type mice receiving equal amount of CVB3, genetic ablation of CatB (Ctsb-/-) significantly improved survival, reduced inflammatory cell infiltration, decreased serum level of cardiac troponin I, and ameliorated cardiac dysfunction, without altering virus titers in hearts. Conversely, genetic deletion of cystatin C (Cstc-/-), which markedly enhanced CatB levels in hearts, distinctly increased the severity of VMC. Furthermore, compared with the control, we found the inflammasome was activated in the hearts of wild-type mice with VMC, which was attenuated in the hearts of Ctsb-/- mice but was further enhanced in Cstc-/- mice. Consistently, the inflammasome-initiated pyroptosis was reduced in Ctsb-/- mice hearts and further increased in Cstc-/- mice. These results suggest that CatB aggravates CVB3-induced VMC probably through activating the inflammasome and promoting pyroptosis. This finding might provide a novel strategy for VMC treatment.
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Catepsina B/fisiologia , Infecções por Coxsackievirus/complicações , Enterovirus Humano B/fisiologia , Inflamassomos/metabolismo , Miocardite/virologia , Piroptose/fisiologia , Animais , Caspase 1/metabolismo , Catepsina B/genética , Infecções por Coxsackievirus/patologia , Modelos Animais de Doenças , Progressão da Doença , Ativação Enzimática , Células HeLa , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocardite/imunologia , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Miócitos Cardíacos/virologiaRESUMO
Patients with heart failure (HF) are prone to combine with renal insufficiency. Recently, LCZ696 has been used in the treatment of HF, but whether LCZ696 is better than angiotensin converting enzyme inhibitors/angiotensin receptor antagonists (ACEI/ARB) in renal protection for HF patients has not been investigated. Therefore, we conducted a meta-analysis focusing on LCZ696 and its role in preservation of renal function in HF patients. Embase, PubMed, the Cochrane Library and ClinicalTrials.gov databases were electronically searched for available randomized controlled trials (RCTs). HF patients taking LCZ696 or ACEI/ARB were assessed for renal adverse events. The last search date was Sep 20, 2019. A total of 14959 patients from 6 trials were included in this meta-analysis. As compared to ACEI/ARB, LCZ696 significantly reduced the risk of renal function deterioration (odds ratio 0.77, 95% confidence interval 0.61-0.97, P = 0.02). In summary, LCZ696 may have superior renal protection in HF patients compared with ACEI/ARB.
Assuntos
Aminobutiratos/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Rim/efeitos dos fármacos , Inibidores de Proteases/uso terapêutico , Tetrazóis/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Aminobutiratos/efeitos adversos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Compostos de Bifenilo , Combinação de Medicamentos , Medicina Baseada em Evidências , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Humanos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Neprilisina/antagonistas & inibidores , Inibidores de Proteases/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Tetrazóis/efeitos adversos , Resultado do Tratamento , ValsartanaRESUMO
RATIONALE: To date, our understanding of the role of HO-1 (heme oxygenase-1) in inflammatory diseases has mostly been limited to its catalytic function and the potential for its heme-related catabolic products to suppress inflammation and oxidative stress. Whether and how HO-1 in macrophages plays a role in the development of septic cardiac dysfunction has never been explored. OBJECTIVE: Here, we investigated the role of macrophage-derived HO-1 in septic cardiac dysfunction. METHODS AND RESULTS: Intraperitoneal injection of lipopolysaccharide significantly activated HO-1 expression in cardiac infiltrated macrophages. Surprisingly, we found that myeloid conditional HO-1 deletion in mice evoked resistance to lipopolysaccharide-triggered septic cardiac dysfunction and lethality in vivo, which was accompanied by reduced cardiomyocyte apoptosis in the septic hearts and decreased peroxynitrite production and iNOS (inducible NO synthase) in the cardiac infiltrated macrophages, whereas proinflammatory cytokine production and macrophage infiltration were unaltered. We further demonstrated that HO-1 suppression abolished the lipopolysaccharide-induced iNOS protein rather than mRNA expression in macrophages. Moreover, we confirmed that the inhibition of HO-1 promoted iNOS degradation through a lysosomal rather than proteasomal pathway in macrophages. Suppression of the lysosomal degradation of iNOS by bafilomycin A1 drove septic cardiac dysfunction in myeloid HO-1-deficient mice. Mechanistically, we demonstrated that HO-1 interacted with iNOS at the flavin mononucleotide domain, which further prevented iNOS conjugation with LC3 (light chain 3) and subsequent lysosomal degradation in macrophages. These effects were independent of HO-1's catabolic products: ferrous ion, carbon monoxide, and bilirubin. CONCLUSIONS: Our results indicate that HO-1 in macrophages drives septic cardiac dysfunction. The mechanistic insights provide potential therapeutic targets to treat septic cardiac dysfunction.
Assuntos
Cardiopatias/enzimologia , Heme Oxigenase-1/metabolismo , Lisossomos/metabolismo , Macrófagos/enzimologia , Óxido Nítrico Sintase Tipo II/metabolismo , Sepse/enzimologia , Animais , Determinação da Pressão Arterial , Citocinas/metabolismo , Cardiopatias/induzido quimicamente , Cardiopatias/mortalidade , Heme Oxigenase-1/deficiência , Lipopolissacarídeos , Macrófagos/efeitos dos fármacos , Camundongos , Miocárdio/metabolismo , RNA Mensageiro/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Sepse/induzido quimicamente , Sepse/mortalidadeRESUMO
BACKGROUND: Arrhythmogenic cardiomyopathy (AC) is one of the leading causes for sudden cardiac death (SCD). Recent studies have identified mutations in cardiac desmosomes as key players in the pathogenesis of AC. However, the specific etiology in individual families remains largely unknown. METHODS: A 4-generation family presenting with syncope, lethal ventricular arrhythmia and SCD was recruited. Targeted next generation sequencing (NGS) was performed and validated by Sanger sequencing. Plasmids containing the mutation and wild type (WT) were constructed. Real-time PCR, western-blot and immunofluorescence were performed to detect the functional change due to the mutation. RESULTS: The proband, a 56-year-old female, presented with recurrent palpitations and syncope. An ICD was implanted due to her family history of SCD/ aborted SCD. NGS revealed a novel heterozygous frame-shift variant (c.832delG) in Desmoplakin (DSP) among 5 family members. The variant led to frame-shift and premature termination, producing a truncated protein. Cardiac magnetic resonance (CMR) of the family members carrying the same variant shown myocardium thinning and fatty infiltration in the right ventricular, positive bi-ventricular late gadolinium enhancement and severe RV dysfunction, fulfilling the diagnostic criteria of AC. HEK293T cells transfected with mutant plasmids expressed truncated DSP mRNA and protein, upregulation of nuclear junction plakoglobin (JUP) and downregulation of ß-catenin, when compared with WT. CONCLUSION: We infer that the novel c.832delG variant in DSP was associated with AC in this family, likely through Wnt/ß-catenin signaling pathway.
Assuntos
Arritmias Cardíacas/genética , Cardiomiopatias/genética , Análise Mutacional de DNA , Desmoplaquinas/genética , Mutação da Fase de Leitura , Sequenciamento de Nucleotídeos em Larga Escala , Adolescente , Adulto , Idoso de 80 Anos ou mais , Arritmias Cardíacas/diagnóstico por imagem , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/metabolismo , Cardiomiopatias/fisiopatologia , Morte Súbita Cardíaca/etiologia , Desmoplaquinas/metabolismo , Feminino , Predisposição Genética para Doença , Células HEK293 , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Função Ventricular Direita/genética , Adulto Jovem , beta Catenina/metabolismo , gama Catenina/metabolismoRESUMO
BACKGROUND: Systematic investigation and analysis of cardiovascular health status (CVHS) of Chinese women is rare. This study aimed to assess CVHS and atherosclerotic cardiovascular disease (ASCVD) burden in the Chinese women physicians (CWP) and community-based non-physician cohort (NPC). METHODS: In this prospective, multicenter, observational study, CVHS using the American Heart Association (AHA) defined 7 metrics (such as smoking and fasting glucose) and ASCVD risk factors including hypertension, hyperlipidemia and type-2 diabetes were evaluated in CWP compared with NPC. RESULTS: Of 5832 CWP with a mean age of 44 ± 7 years, only 1.2% achieved the ideal CVHS and 90.1% showed at least 1 of the 7 AHA CVHS metrics at a poor level. Total CVHS score was significantly decreased and ASCVD risk burden was increased in postmenopausal subjects in CWP although ideal CVHS was not significantly influenced by menopause. Compared to 2596 NPC, fewer CWP had ≥ 2 risk factors (8% vs. 27%, P < 0.001); CWP scored significantly higher on healthy factors, a composite of total cholesterol, blood pressure, fasting glucose (P < 0.001), but, poorly on healthy behaviors (P < 0.001), specifically in the physical activity component; CWP also showed significantly higher levels of awareness and rates of treatment for hypertension and hyperlipidemia, but, not for type-2 diabetes. CONCLUSION: Chinese women's cardiovascular health is far from ideal and risk intervention is sub-optimal. Women physicians had lower ASCVD burden, scored higher in healthy factors, but, took part in less physical activity than the non-physician cohort. These results call for population-specific early and improved risk intervention.
Assuntos
Aterosclerose/epidemiologia , Nível de Saúde , Médicas , Saúde da Mulher , Mulheres Trabalhadoras , Adulto , Aterosclerose/diagnóstico , Aterosclerose/prevenção & controle , China/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/terapia , Dislipidemias/epidemiologia , Dislipidemias/terapia , Estilo de Vida Saudável , Fatores de Risco de Doenças Cardíacas , Humanos , Hipertensão/epidemiologia , Hipertensão/terapia , Masculino , Menopausa , Pessoa de Meia-Idade , Serviços Preventivos de Saúde , Estudos Prospectivos , Fatores de Proteção , Medição de Risco , Comportamento de Redução do Risco , Fatores SexuaisRESUMO
BACKGROUND: Extracellular matrix metabolism and cardiac cell death participate centrally in myocardial infarction (MI). This study tested the roles of collagenolytic cathepsin K (CatK) in post-MI left ventricular remodeling. METHODS AND RESULTS: Patients with acute MI had higher plasma CatK levels (20.49⯱â¯7.07â¯pmol/L, nâ¯=â¯26) than those in subjects with stable angina pectoris (8.34⯱â¯1.66â¯pmol/L, nâ¯=â¯28, Pâ¯=â¯.01) or those without coronary heart disease (6.63⯱â¯0.84â¯pmol/L, nâ¯=â¯93, Pâ¯=â¯.01). CatK protein expression increases in mouse hearts at 7 and 28â¯days post-MI. Immunofluorescent staining localized CatK expression in cardiomyocytes, endothelial cells, fibroblasts, macrophages, and CD4+ T cells in infarcted mouse hearts at 7â¯days post-MI. To probe the direct participation of CatK in MI, we produced experimental MI in CatK-deficient mice (Ctsk-/-) and their wild-type (Ctsk+/+) littermates. CatK-deficiency yielded worsened cardiac function at 7 and 28â¯days post-MI, compared to Ctsk+/+ littermates (fractional shortening percentage: 5.01⯱â¯0.68 vs. 8.62⯱â¯1.04, Pâ¯<â¯.01, 7â¯days post-MI; 4.32⯱â¯0.52 vs. 7.60⯱â¯0.82, Pâ¯<â¯.01, 28â¯days post-MI). At 7â¯days post-MI, hearts from Ctsk-/- mice contained less CatK-specific type-I collagen fragments (10.37⯱â¯1.91 vs. 4.60⯱â¯0.49â¯ng/mg tissue extract, Pâ¯=â¯.003) and more fibrosis (1.67⯱â¯0.93 vs. 0.69⯱â¯0.20 type-III collagen positive area percentage, Pâ¯=â¯.01; 14.25⯱â¯4.12 vs. 6.59⯱â¯0.79 α-smooth muscle actin-positive area percentage, Pâ¯=â¯.016; and 0.82⯱â¯0.06 vs. 0.31⯱â¯0.08 CD90-positive area percentage, Pâ¯=â¯.008) than those of Ctsk+/+ mice. Immunostaining demonstrated that CatK-deficiency yielded elevated cardiac cell death but reduced cardiac cell proliferation. In vitro studies supported a role of CatK in cardiomyocyte survival. CONCLUSION: Plasma CatK levels are increased in MI patients. Heart CatK expression is also elevated post-MI, but CatK-deficiency impairs post-MI cardiac function in mice by increasing myocardial fibrosis and cardiomyocyte death.
Assuntos
Catepsina K/deficiência , Testes de Função Cardíaca , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/fisiopatologia , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/enzimologia , Síndrome Coronariana Aguda/fisiopatologia , Idoso , Animais , Apoptose , Catepsina K/sangue , Proliferação de Células , Colágeno/metabolismo , Feminino , Fibrose , Ventrículos do Coração/metabolismo , Humanos , Inflamação/patologia , Masculino , Camundongos , Pessoa de Meia-IdadeRESUMO
EphrinB2, a membrane-tethered ligand preferentially binding to its receptor EphB4, is ubiquitously expressed in all mammals. Through the particular bidirectional signaling, EphrinB2 plays a critical role during the development of cardiovascular system, postnatal angiogenesis physiologically and pathologically, and cardiac remodeling after injuries as an emerging role. This review highlights the pivotal involvement of EphrinB2 in heart, from developmental cardiogenesis to pathological cardiac remodeling process. Further potential translational therapies will be discussed in targeting EphrinB2 signaling, to better understand the prevention and treatment of cardiovascular diseases.