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Early research suggested that bone morphogenetic protein 10 (BMP10) is primarily involved in cardiac development and congenital heart disease processes. BMP10 is a newly identified cardiac-specific protein. In recent years, reports have emphasized the effects of BMP10 on myocardial apoptosis, fibrosis and immune response, as well as its synergistic effects with BMP9 in vascular endothelium and role in endothelial dysfunction. We believe that concentrating on this aspect of the study will enhance our knowledge of the pathogenesis of diabetes and the cardiovascular field. However, there have been no reports of any reviews discussing the role of BMP10 in diabetes and cardiovascular disease. In addition, the exact pathogenesis of diabetic cardiomyopathy is not fully understood, including myocardial energy metabolism disorders, microvascular changes, abnormal apoptosis of cardiomyocytes, collagen structural changes and myocardial fibrosis, all of which cause cardiac function impairment directly or indirectly and interact with one another. This review summarizes the research results of BMP10 in cardiac development, endothelial function and cardiovascular disease in an effort to generate new ideas for future research into diabetic cardiomyopathy.
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Proteínas Morfogenéticas Ósseas , Doenças Cardiovasculares , Diabetes Mellitus , Cardiomiopatias Diabéticas , Humanos , Animais , Proteínas Morfogenéticas Ósseas/metabolismo , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , ApoptoseRESUMO
BACKGROUND: Serum bone morphogenetic protein 10 (BMP10) blood levels are a marker for history of atrial fibrillation (AF) and for major adverse cardiovascular events in patients with AF, including stroke, AF recurrences after catheter ablations, and mortality. The predictive value of BMP10 in patients undergoing cardiac surgery and association with morphologic properties of atrial tissues are unknown. OBJECTIVES: This study sought to study the correlation between BMP10 levels and preoperative clinical traits, occurrence of early and late postoperative atrial fibrillation (POAF), and atrial fibrosis in patients undergoing cardiac surgery. METHODS: Patients with and without preoperative AF history undergoing first cardiac surgery were included (RACE V, n = 147). Preoperative blood biomarkers were analyzed, left (n = 114) and right (n = 125) atrial appendage biopsy specimens were histologically investigated after WGA staining, and postoperative rhythm was monitored continuously with implantable loop recorders (n = 133, 2.5 years). RESULTS: Adjusted multinomial logistic regression indicated that BMP10 accurately reflected a history of persistent AF (OR: 1.24, 95% CI: 1.10-1.40, P = 0.001), similar to NT-pro-BNP. BMP10 levels were associated with increased late POAF90 occurrence after adjustment for age, sex, AF history, and early POAF occurrence (HR: 1.07 [per 0.1 ng/mL increase], 95% CI: 1.00-1.14, P = 0.041). Left atrial endomysial fibrosis (standardized ß = 0.22, P = 0.041) but not overall fibrosis (standardized Β = 0.12, P = 0.261) correlated with circulating BMP10 after adjustment for age, sex, AF history, reduced LVF, and valvular surgery indication. CONCLUSIONS: Increased BMP10 levels were associated with persistent AF history, increased late POAF incidence, and LAA endomysial fibrosis in a diverse sample of patients undergoing cardiac surgery.
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Fibrilação Atrial , Procedimentos Cirúrgicos Cardíacos , Complicações Pós-Operatórias , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Apêndice Atrial/cirurgia , Fibrilação Atrial/sangue , Fibrilação Atrial/epidemiologia , Biomarcadores/sangue , Proteínas Morfogenéticas Ósseas , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Fibrose , Átrios do Coração/patologia , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/epidemiologiaRESUMO
BACKGROUND: BMP10 (bone morphogenic protein 10) has emerged as a novel biomarker associated with the risk of ischemic stroke and other outcomes in patients with atrial fibrillation (AF). The study aimed to determine if repeated BMP10 measurements improve prognostication of cardiovascular events in patients with AF. METHODS AND RESULTS: BMP10 was measured using a prototype Elecsys immunoassay in plasma samples collected at randomization and after 2 months in patients with AF randomized to apixaban or warfarin in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial (n=2878). Adjusted Cox-regression models were used to evaluate the association between 2-month BMP10 levels and outcomes. BMP10 levels increased by 7.8% (P<0.001) over 2 months. The baseline variables most strongly associated with BMP10 levels at 2 months were baseline BMP10 levels, body mass index, sex, age, creatinine, diabetes, warfarin treatment, and AF-rhythm. During median 1.8 years follow-up, 34 ischemic strokes/systemic embolism, 155 deaths, and 99 heart failure hospitalizations occurred. Comparing the third with the first sample quartile, higher BMP10 levels at 2 months were associated with higher risk of ischemic stroke (hazard ratio [HR], 1.33 [95% CI, 0.67-2.63], P=0.037), heart failure (HR, 1.91 [95% CI, 1.17-3.12], P=0.012) and all-cause death (HR, 1.61 [95% CI, 1.17-2.21], P<0.001). Adding BMP10 levels at 2 months on top of established risk factors and baseline BMP10 levels improved the C-indices for ischemic stroke/systemic embolism (from 0.73 to 0.75), heart failure hospitalization (0.76-0.77), and all-cause mortality (0.70-0.72), all P<0.05. CONCLUSIONS: Elevated levels of BMP10 at 2 months strengthened the associations with the risk of ischemic stroke, hospitalization for heart failure, and all-cause mortality. Repeated measurements of BMP10 may further refine risk stratification in patients with AF.
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Fibrilação Atrial , Proteínas Morfogenéticas Ósseas , Insuficiência Cardíaca , Acidente Vascular Cerebral , Humanos , Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Fibrilação Atrial/complicações , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/tratamento farmacológico , Biomarcadores , Proteínas Morfogenéticas Ósseas/sangue , Proteínas Morfogenéticas Ósseas/química , Embolia , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/complicações , AVC Isquêmico , Medição de Risco/métodos , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Varfarina/efeitos adversos , Varfarina/uso terapêuticoRESUMO
Background: The association between bone morphogenetic protein 10 (BMP10) and atrial fibrillation (AF) has been widely investigated by observational studies, but their causal relationships remain inconclusive. Here, we aimed to evaluate the causal effect of BMP10 on the risk of AF through single-nucleotide polymorphisms. Methods: A Mendelian randomization (MR) analytic framework was applied to data from two BMP10-specific genome-wide association studies comprising a total of 11,036,163 single-nucleotide polymorphisms of European ancestry. Instrument genetic variants associated with BMP10 were selected. A total of 12 AF-specific genome-wide association studies comprising a total of 5,095,117 European participants were included. Summary statistic-based methods of inverse variance weighted, MR Egger, weighted median, simple mode, and weighted mode methods were used. Pleiotropy and sensitivity were assessed. Results: Specific to AF-specific genome-wide association studies, we found that BMP10 was not associated with AF among different methods (all P > 0.05). We further identified no significant horizontal pleiotropy (all P > 0.05) and no fundamental impact among various data. Conclusions: This large-scale population study upon data from BMP10- and AF-specific genome-wide association studies and a longitudinal biobank cohort indicates plausible non-causal associations between BMP10 and AF in the European populations. Further studies regarding ancestral diversity are warranted to validate such causal associations.
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BACKGROUND: BMP9 and BMP10 are two major regulators of vascular homeostasis. These two ligands bind with high affinity to the endothelial type I kinase receptor ALK1, together with a type II receptor, leading to the direct phosphorylation of the SMAD transcription factors. Apart from this canonical pathway, little is known. Interestingly, mutations in this signaling pathway have been identified in two rare cardiovascular diseases, hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension. METHODS: To get an overview of the signaling pathways modulated by BMP9 and BMP10 stimulation in endothelial cells, we employed an unbiased phosphoproteomic-based strategy. Identified phosphosites were validated by western blot analysis and regulated targets by RT-qPCR. Cell cycle analysis was analyzed by flow cytometry. RESULTS: Large-scale phosphoproteomics revealed that BMP9 and BMP10 treatment induced a very similar phosphoproteomic profile. These BMPs activated a non-canonical transcriptional SMAD-dependent MAPK pathway (MEKK4/P38). We were able to validate this signaling pathway and demonstrated that this activation required the expression of the protein GADD45ß. In turn, activated P38 phosphorylated the heat shock protein HSP27 and the endocytosis protein Eps15 (EGF receptor pathway substrate), and regulated the expression of specific genes (E-selectin, hyaluronan synthase 2 and cyclooxygenase 2). This study also highlighted the modulation in phosphorylation of proteins involved in transcriptional regulation (phosphorylation of the endothelial transcription factor ERG) and cell cycle inhibition (CDK4/6 pathway). Accordingly, we found that BMP10 induced a G1 cell cycle arrest and inhibited the mRNA expression of E2F2, cyclinD1 and cyclinA1. CONCLUSIONS: Overall, our phosphoproteomic screen identified numerous proteins whose phosphorylation state is impacted by BMP9 and BMP10 treatment, paving the way for a better understanding of the molecular mechanisms regulated by BMP signaling in vascular diseases.
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Proteínas Morfogenéticas Ósseas , Células Endoteliais , Pontos de Checagem do Ciclo Celular , Fosforilação , Pontos de Checagem da Fase G1 do Ciclo CelularRESUMO
OBJECTIVE: Aggregating evidence convincingly establishes the predominant genetic basis underlying congenital heart defects (CHD), though the heritable determinants contributing to CHD in the majority of cases remain elusive. In the current investigation, BMP10 was selected as a prime candidate gene for human CHD mainly due to cardiovascular developmental abnormalities in Bmp10-knockout animals. The objective of this retrospective study was to identify a new BMP10 mutation responsible for CHD and characterize the functional effect of the identified CHD-causing BMP10 mutation. METHODS: Sequencing assay of BMP10 was fulfilled in a cohort of 276 probands with various CHD and a total of 288 non-CHD volunteers. The available family members from the proband harboring an identified BMP10 mutation were also BMP10-genotyped. The effect of the identified CHD-causative BMP10 mutation on the transactivation of TBX20 and NKX2.5 by BMP10 was quantitatively analyzed in maintained HeLa cells utilizing a dual-luciferase reporter assay system. RESULTS: A novel heterozygous BMP10 mutation, NM_014482.3:c.247G>T;p.(Glu83*), was identified in one proband with patent ductus arteriosus (PDA), which was confirmed to co-segregate with the PDA phenotype in the mutation carrier's family. The nonsense mutation was not observed in 288 non-CHD volunteers. Functional analysis unveiled that Glu83*-mutant BMP10 had no transactivation on its two representative target genes TBX20 and NKX2.5, which were both reported to cause CHD. CONCLUSION: These findings provide strong evidence indicating that genetically compromised BMP10 predisposes human beings to CHD, which sheds light on the new molecular mechanism that underlies CHD and allows for antenatal genetic counseling and individualized precise management of CHD.
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Maternal hypothyroidism (MH) could adversely affect the cardiac disease responses of the progeny. This study tested the hypothesis that MH reduces early postnatal cardiomyocyte (CM) proliferation so that the adult heart of MH progeny has a smaller number of larger cardiac myocytes, which imparts adverse cardiac disease responses following injury. Thyroidectomy (TX) was used to establish MH. The progeny from mice that underwent sham or TX surgery were termed Ctrl (control) or MH (maternal hypothyroidism) progeny, respectively. MH progeny had similar heart weight (HW) to body weight (BW) ratios and larger CM size consistent with fewer CMs at postnatal day 60 (P60) compared with Ctrl (control) progeny. MH progeny had lower numbers of EdU+, Ki67+, and phosphorylated histone H3 (PH3)+ CMs, which suggests they had a decreased CM proliferation in the postnatal timeframe. RNA-seq data showed that genes related to DNA replication were downregulated in P5 MH hearts, including bone morphogenetic protein 10 (Bmp10). Both in vivo and in vitro studies showed Bmp10 treatment increased CM proliferation. After transverse aortic constriction (TAC), the MH progeny had more severe cardiac pathological remodeling compared with the Ctrl progeny. Thyroid hormone (T4) treatment for MH mothers preserved their progeny's postnatal CM proliferation capacity and prevented excessive pathological remodeling after TAC. Our results suggest that CM proliferation during early postnatal development was significantly reduced in MH progeny, resulting in fewer CMs with hypertrophy in adulthood. These changes were associated with more severe cardiac disease responses after pressure overload.NEW & NOTEWORTHY Our study shows that compared with Ctrl (control) progeny, the adult progeny of mothers who have MH (MH progeny) had fewer CMs. This reduction of CM numbers was associated with decreased postnatal CM proliferation. Gene expression studies showed a reduced expression of Bmp10 in MH progeny. Bmp10 has been linked to myocyte proliferation. In vivo and in vitro studies showed that Bmp10 treatment of MH progeny and their myocytes could increase CM proliferation. Differences in CM number and size in adult hearts of MH progeny were linked to more severe cardiac structural and functional remodeling after pressure overload. T4 (synthetic thyroxine) treatment of MH mothers during their pregnancy, prevented the reduction in CM number in their progeny and the adverse response to disease stress.
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Cardiopatias , Hipotireoidismo , Gravidez , Feminino , Camundongos , Animais , Miócitos Cardíacos/metabolismo , Cardiopatias/patologia , Hipertrofia/metabolismo , Hipertrofia/patologia , Hipotireoidismo/complicações , Hipotireoidismo/metabolismo , Hipotireoidismo/patologia , Proteínas Morfogenéticas Ósseas/metabolismo , Proliferação de Células , Cardiomegalia/metabolismoRESUMO
AIMS: Atrial remodelling, defined as a change in atrial structure, promotes atrial fibrillation (AF). Bone morphogenetic protein 10 (BMP10) is an atrial-specific biomarker released to blood during atrial development and structural changes. We aimed to validate whether BMP10 is associated with AF recurrence after catheter ablation (CA) in a large cohort of patients. METHODS AND RESULTS: We measured baseline BMP10 plasma concentrations in AF patients who underwent a first elective CA in the prospective Swiss-AF-PVI cohort study. The primary outcome was AF recurrence lasting longer than 30â s during a follow-up of 12 months. We constructed multivariable Cox proportional hazard models to determine the association of BMP10 and AF recurrence. A total of 1112 patients with AF (age 61 ± 10 years, 74% male, 60% paroxysmal AF) was included in our analysis. During 12 months of follow-up, 374 patients (34%) experienced AF recurrence. The probability for AF recurrence increased with increasing BMP10 concentration. In an unadjusted Cox proportional hazard model, a per-unit increase in log-transformed BMP10 was associated with a hazard ratio (HR) of 2.28 (95% CI 1.43; 3.62, P < 0.001) for AF recurrence. After multivariable adjustment, the HR of BMP10 for AF recurrence was 1.98 (95% CI 1.14; 3.42, P = 0.01), and there was a linear trend across BMP10 quartiles (P = 0.02 for linear trend). CONCLUSION: The novel atrial-specific biomarker BMP10 was strongly associated with AF recurrence in patients undergoing CA for AF. CLINICALTRIALS.GOV IDENTIFIER: NCT03718364; https://clinicaltrials.gov/ct2/show/NCT03718364.
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Fibrilação Atrial , Ablação por Cateter , Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Feminino , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/cirurgia , Estudos de Coortes , Estudos Prospectivos , Proteínas Morfogenéticas Ósseas , Ablação por Cateter/efeitos adversosRESUMO
Background Patients with atrial fibrillation (AF) face an increased risk of death and major adverse cardiovascular events (MACE). We aimed to assess the predictive value of the novel atrial-specific biomarker BMP10 (bone morphogenetic protein 10) for death and MACE in patients with AF in comparison with NT-proBNP (N-terminal prohormone of B-type natriuretic peptide). Methods and Results BMP10 and NT-proBNP were measured in patients with AF enrolled in Swiss-AF (Swiss Atrial Fibrillation Study), a prospective multicenter cohort study. A total of 2219 patients were included (median follow-up 4.3 years [interquartile range 3.9, 5.1], mean age 73±9 years, 73% male). In multivariable Cox proportional hazard models, the adjusted hazard ratio (aHR) associated with 1 ng/mL increase of BMP10 was 1.60 (95% CI, 1.37-1.87) for all-cause death, and 1.54 (95% CI, 1.35-1.76) for MACE. For all-cause death, the concordance index was 0.783 (95% CI, 0.763-0.809) for BMP10, 0.784 (95% CI, 0.765-0.810) for NT-proBNP, and 0.789 (95% CI, 0.771-0.815) for both biomarkers combined. For MACE, the concordance index was 0.732 (95% CI, 0.715-0.754) for BMP10, 0.747 (95% CI, 0.731-0.768) for NT-proBNP, and 0.750 (95% CI, 0.734-0.771) for both biomarkers combined. When grouping patients according to NT-proBNP categories (<300, 300-900, >900 ng/L), higher aHRs were observed in patients with high BMP10 in the categories of low NT-proBNP (all-cause death aHR, 2.28 [95% CI, 1.15-4.52], MACE aHR, 1.88 [95% CI, 1.07-3.28]) and high NT-proBNP (all-cause death aHR, 1.61 [95% CI, 1.14-2.26], MACE aHR, 1.38 [95% CI, 1.07-1.80]). Conclusions BMP10 strongly predicted all-cause death and MACE in patients with AF. BMP10 provided additional prognostic information in low- and high-risk patients according to NT-proBNP stratification. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02105844.
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Fibrilação Atrial , Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/complicações , Estudos de Coortes , Estudos Prospectivos , Biomarcadores , Prognóstico , Fragmentos de Peptídeos , Peptídeo Natriurético Encefálico , Proteínas Morfogenéticas ÓsseasRESUMO
Dilated cardiomyopathy (DCM), characterized by left ventricular or biventricular enlargement with systolic dysfunction, is the most common type of cardiac muscle disease. It is a major cause of congestive heart failure and the most frequent indication for heart transplantation. Aggregating evidence has convincingly demonstrated that DCM has an underlying genetic basis, though the genetic defects responsible for DCM in a larger proportion of cases remain elusive, motivating the ongoing research for new DCM-causative genes. In the current investigation, a multigenerational family affected with autosomal-dominant DCM was recruited from the Chinese Han population. By whole-exome sequencing and Sanger sequencing analyses of the DNAs from the family members, a new BMP10 variation, NM_014482.3:c.166C > T;p.(Gln56*), was discovered and verified to be in co-segregation with the DCM phenotype in the entire family. The heterozygous BMP10 variant was not detected in 268 healthy volunteers enrolled as control subjects. The functional measurement via dual-luciferase reporter assay revealed that Gln56*-mutant BMP10 lost the ability to transactivate its target genes NKX2.5 and TBX20, two genes that had been causally linked to DCM. The findings strongly indicate BMP10 as a new gene contributing to DCM in humans and support BMP10 haploinsufficiency as an alternative pathogenic mechanism underpinning DCM, implying potential implications for the early genetic diagnosis and precision prophylaxis of DCM.
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BACKGROUND: Cardiac hypertrophy can lead to cardiac dysfunction and is closely associated with mortality in diabetic cardiomyopathy (DCM). Astragalus polysaccharides (APS) is the main component extracted from Astragalus membranaceus (Fisch.) Bunge (AM), which exhibits anti-hypertrophic effects on cardiomyocytes in various diseases. However, whether APS exerts anti-hypertrophic effects in DCM remains unclear. PURPOSE: To investigate whether APS can attenuate cardiac hypertrophy in DCM and exert anti-hypertrophic effects by inhibiting the bone morphogenetic protein 10 (BMP10) pathway. METHODS: The anti-hypertrophic effects of APS were studied in high-glucose (HG)-stimulated H9c2 cardiomyocytes and streptozotocin (STZ)-induced DCM rats. BMP10 siRNA was used to inhibit BMP10 expression in H9c2 cardiomyocytes. Cardiac function was assessed by echocardiography. Cardiac hypertrophy was evaluated using heart weight/body weight (HW/BW), RT-PCR, hematoxylin-eosin (HE), and rhodamine phalloidin staining. Changes in hypertrophic components, including BMP10 and downstream factors, were measured using western blotting. RESULTS: In vitro, HG treatment increased the relative cell surface area of H9c2 cardiomyocytes, whereas BMP10 siRNA transfection or APS treatment alleviated the increase induced by HG. APS treatment improved the general condition, increased cardiac function, and decreased the HW/BW ratio, ANP mRNA level, and cardiomyocyte cross-sectional area of DCM rats in vivo. Molecular experiments demonstrated that APS downregulated the levels of the pro-hypertrophic protein BMP10 and its downstream proteins ALK3, BMPRII, and p-Smad1/5/8 without affecting the level of total Smad1/5/8. CONCLUSIONS: Our study demonstrates that APS can alleviate cardiac hypertrophy and protect against DCM by inhibiting activation of the BMP10 pathway. APS is a promising candidate for DCM treatment.
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Astrágalo , Diabetes Mellitus , Cardiomiopatias Diabéticas , Ratos , Animais , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/metabolismo , Cardiomegalia/induzido quimicamente , Transdução de Sinais , Miócitos Cardíacos , Polissacarídeos/farmacologia , RNA Interferente Pequeno/farmacologia , Proteínas Morfogenéticas Ósseas/metabolismo , Diabetes Mellitus/tratamento farmacológicoRESUMO
AIMS: Biomarkers specifically related to atrial tissue may increase the understanding of the pathophysiology of atrial fibrillation (AF) and further improve risk prediction in this setting. Bone morphogenetic protein 10 (BMP10) is a protein expressed in the atrial myocardium. We evaluated the association between BMP10 and the risk of ischaemic stroke and other cardiovascular events in large cohorts of patients with AF, treated with and without oral anticoagulation (OAC). METHODS AND RESULTS: BMP10 was measured in plasma samples collected at randomisation in patients with AF without OAC in the ACTIVE A and AVERROES trials (n = 2974), and with OAC in the ARISTOTLE trial (n = 13 079). BMP10 was analysed with a prototype Elecsys immunoassay. Associations with outcomes were evaluated by Cox-regression models adjusted for clinical characteristics, kidney function, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Median concentrations of BMP10 were 2.47 and 2.44 ng/mL, in the non-OAC and OAC cohort, respectively. Increasing BMP10 was associated with lower body mass index, older age, female sex, kidney dysfunction, and AF rhythm. BMP10 was consistently associated with ischaemic stroke. In the non-OAC cohort, BMP10 increased the concordance index of the multivariable model from 0.713 to 0.733 (P = 0.004) and in the OAC cohort from 0.673 to 0.694 (P < 0.001). Additionally, BMP10 maintained a significant prognostic value after additionally adjusting for NT-proBNP. BMP10 was not independently associated with bleeding or with death. CONCLUSION: The novel atrial biomarker BMP10 was independently associated with ischaemic stroke in patients with AF irrespective of OAC treatment. BMP10 seems to be more specifically related to the risk of ischaemic stroke in AF. ONE-SENTENCE SUMMARY: In this study, BMP10 may be a novel specific biomarker of ischaemic stroke in patients with atrial fibrillation, irrespective of oral anticoagulation.
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Fibrilação Atrial , Proteínas Morfogenéticas Ósseas , Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Feminino , Humanos , Anticoagulantes , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Biomarcadores , Isquemia Encefálica/induzido quimicamente , AVC Isquêmico/induzido quimicamente , AVC Isquêmico/complicações , AVC Isquêmico/tratamento farmacológico , Fatores de Risco , Acidente Vascular Cerebral/induzido quimicamente , MasculinoRESUMO
NF-κB is a major transcription factor regulating cell survival, organ development and inflammation, but its role in cardiac development has been inadequately explored. To examine this function, we generated mice in which IKKß, an essential kinase for NF-κB activation, was constitutively activated in embryonic cardiomyocytes. For this purpose, we used smooth muscle-22α (SM22α)-Cre mice, which are frequently used for gene recombination in embryonic cardiomyocytes. Embryonic hearts of SM22αCre-CA (constitutively active) IKKßflox/flox mice revealed remarkably thin, spongy and hypoplastic myocardium. In exploring the mechanism, we found that the expression of bone morphogenetic protein 10 (BMP10) and T-box transcription factor 20 (Tbx20), major regulators of cardiac development, was significantly downregulated and upregulated, respectively, in the SM22αCre-CAIKKßflox/flox mice. We also generated NK2 homeobox 5 (Nkx2.5) Cre-CAIKKßflox/wt mice since Nkx2.5 is also expressed in embryonic cardiomyocytes and confirmed that the changes in these genes were also observed. These results implicated that the activation of NF-κB affects cardiac development.
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Coração , Quinase I-kappa B , NF-kappa B , Animais , Proteínas Morfogenéticas Ósseas/metabolismo , Coração/embriologia , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Camundongos , Miocárdio/metabolismo , NF-kappa B/metabolismo , Proteínas com Domínio T/metabolismo , Fatores de Transcrição/metabolismoRESUMO
Doxorubicin (DOX) has limited antitumor applications owing to its association with life-threatening cardiac injury. Oxidative damage and cardiac apoptosis are crucial in DOX-induced cardiac injury. Bone morphogenetic protein 10 (BMP10) is predominantly distributed in the heart and acts as a cardioprotective factor that preserves cardiac function. However, the role of BMP10 in DOX-induced cardiac injury has not yet been explored. The current study aimed to examine the function and mechanism of action of BMP10 in DOX-induced cardiac injury. An adeno-associated viral system was used for the overexpression or silencing of cardiac-specific BMP10, and subsequently, a single dose of DOX was intraperitoneally injected to induce cardiac injury. Results showed that DOX exposure decreased BMP10 expression in the heart. Cardiac-specific overexpression of BMP10 alleviated the oxidative stress and apoptosis and improved cardiac function. Conversely, cardiac-specific silencing of BMP10 aggravated the redox disorder and apoptosis and worsened the cardiac dysfunction caused by DOX. Exogenous BMP10 supplementation amelioratesd the DOX-induced cardiac contractile dysfunction. Mechanistically, we found that phosphorylation of signal transducer and activator of transcription 3 (STAT3) is reduced in DOX-induced cardiotoxicity, and, BMP10 activated impaired STAT3 via a non-canonical pathway. BMP10 lost its cardioprotective function in cardiomyocyte-specific STAT3 knockout (STAT3-cKO) mice. Based on our findings, we suggested that BMP10 is a potential therapeutic agent against DOX-induced cardiac injury and that the cardioprotective effects of BMP10 are dependent on the activation of STAT3.
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Cardiopatias , Fator de Transcrição STAT3 , Animais , Apoptose , Proteínas Morfogenéticas Ósseas/metabolismo , Proteínas Morfogenéticas Ósseas/farmacologia , Cardiotoxicidade/metabolismo , Doxorrubicina/efeitos adversos , Cardiopatias/metabolismo , Camundongos , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de SinaisRESUMO
Bone morphogenetic protein 10 (BMP10), is a member of the transforming growth factor ß (TGFß) superfamily. Although BMP10 plays pivotal roles during development, including vascular development and cardiogenesis, little information is available for BMP10 expression in the central nervous system (CNS). We, thus, investigated BMP10 expression in the adult rat CNS using immunohistochemistry. BMP10 was intensely expressed in most neurons and their axons. Furthermore, we found that astrocytes and ependymal cells also express BMP10 protein. These data indicate that BMP10 is widely expressed throughout the adult CNS, and this abundant expression strongly supports the idea that BMP10 also plays important roles in the adult CNS.
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Encéfalo , Neurônios , Animais , Proteínas Morfogenéticas Ósseas/metabolismo , Encéfalo/metabolismo , Sistema Nervoso Central , Neurônios/metabolismo , Ratos , Ratos WistarRESUMO
Bone morphogenetic proteins (BMPs) are dimeric transforming growth factor ß (TGFß) family cytokines that were first described in bone and cartilage formation but have since been shown to be involved in many pleiotropic functions. In human, there are 15 BMP ligands, which initiate their cellular signaling by forming a complex with two copies of type I receptors and two copies of type II receptors, both of which are transmembrane receptors with an intracellular serine/threonine kinase domain. Within this receptor family, ALK1 (activin receptor-like kinase 1), which is a type I receptor mainly expressed on endothelial cells, and BMPRII (BMP Receptor type II), a type II receptor also highly expressed on endothelial cells, have been directly linked to two rare vascular diseases: hereditary hemorrhagic telangiectasia (HHT), and pulmonary arterial hypertension (PAH), respectively. BMP9 (gene name GDF2) and BMP10, two close members of the BMP family, are the only known ligands for the ALK1 receptor. This specificity gives them a unique role in physiological and pathological angiogenesis and tissue homeostasis. The aim of this current review is to present an overview of what is known about BMP9 and BMP10 on vascular regulation with a particular emphasis on recent results and the many questions that remain unanswered regarding the roles and specificities between BMP9 and BMP10.
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Células Endoteliais , Fator 2 de Diferenciação de Crescimento , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Células Endoteliais/metabolismo , Fator 2 de Diferenciação de Crescimento/genética , Fator 2 de Diferenciação de Crescimento/metabolismo , Humanos , Transdução de Sinais/fisiologiaRESUMO
BMP10 plays an essential role in regulating cardiac growth, chamber maturation, and maintaining normal expressions of several key cardiogenic factors; however, other functional roles of BMP10 in muscle remain unexplored. This study therefore undertook to investigate the roles of BMP10 in muscle physiology, using mouse-derived C2C12 myoblasts. Bmp10 silencing prevented a number of biological processes such as myogenic differentiation, glucose uptake, and lipid catabolism, whereas exogenous induction of BMP10 in C2C12 cells significantly stimulated the expression of proteins and genes involved in these processes, as well as mitochondrial biogenesis and thermogenesis, resulting in reduced lipid accumulation. A mechanistic study revealed that BMP10 stimulates myogenesis mainly via the Smad 1/5/8 signaling pathway. In conclusion, our data unveiled a previously unknown mechanism in the regulation of lipid metabolisms by BMP10 in muscle cells and identified its significant roles in systemic metabolic homeostasis, shedding light on BMP10 as a pharmacotherapeutic target to treat metabolic disorders.
Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Diferenciação Celular , Desenvolvimento Muscular , Mioblastos/metabolismo , Transdução de Sinais , Proteína Smad1/metabolismo , Proteína Smad5/metabolismo , Proteína Smad8/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/genética , Linhagem Celular , Camundongos , Proteína Smad1/genética , Proteína Smad5/genética , Proteína Smad8/genéticaRESUMO
Early life stages of fish are highly sensitive to crude oil exposure and thus, short term exposures during critical developmental periods could have detrimental consequences for juvenile survival. Here we administered crude oil to Atlantic haddock (Melanogrammus aeglefinus) in short term (3-day) exposures at two developmental time periods: before first heartbeat, from gastrulation to cardiac cone stage (early), and from first heartbeat to one day before hatching (late). A frequent sampling regime enabled us to determine immediate PAH uptake, metabolite formation and gene expression changes. In general, the embryotoxic consequences of an oil exposure were more severe in the early exposure animals. Oil droplets on the eggshell resulted in severe cardiac and craniofacial abnormalities in the highest treatments. Gene expression changes of Cytochrome 1 a, b, c and d (cyp1a, b, c, d), Bone morphogenetic protein 10 (bmp10), ABC transporter b1 (abcb1) and Rh-associated G-protein (rhag) were linked to PAH uptake, occurrence of metabolites of phenanthrene and developmental and functional abnormalities. We detected circulation-independent, oil-induced gene expression changes and separated phenotypes linked to proliferation, growth and disruption of formation events at early and late developmental stages. Changes in bmp10 expression suggest a direct oil-induced effect on calcium homeostasis. Localized expression of rhag propose an impact on osmoregulation. Severe eye abnormalities were linked to possible inappropriate overexpression of cyp1b in the eyes. This study gives an increased knowledge about developmentally dependent effects of crude oil toxicity. Thus, our findings provide more knowledge and detail to new and several existing adverse outcome pathways of crude oil toxicity.
Assuntos
Poluição por Petróleo , Petróleo , Hidrocarbonetos Policíclicos Aromáticos , Poluentes Químicos da Água , Animais , Expressão Gênica , Petróleo/análise , Petróleo/toxicidade , Poluição por Petróleo/efeitos adversos , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Água , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidadeRESUMO
BACKGROUND: The peptide apelin is expressed in human healthy livers and is implicated in the development of hepatic fibrosis and cirrhosis. Mutations in the bone morphogenetic protein receptor type II (BMPR-II) result in reduced plasma levels of apelin in patients with heritable pulmonary arterial hypertension. Ligands for BMPR-II include bone morphogenetic protein 9 (BMP9), highly expressed in liver, and BMP10, expressed in heart and to a lesser extent liver. However, it is not known whether reductions in BMP9 and/or BMP10, with associated reduction in BMPR-II signalling, correlate with altered levels of apelin in patients with liver fibrosis and cirrhosis. METHODS: Plasma from patients with liver fibrosis (n = 14), cirrhosis (n = 56), and healthy controls (n = 25) was solid-phase extracted using a method optimised for recovery of apelin, which was measured by ELISA. RESULTS: Plasma apelin was significantly reduced in liver fibrosis (8.3 ± 1.2 pg/ml) and cirrhosis (6.5 ± 0.6 pg/ml) patients compared with controls (15.4 ± 2.0 pg/ml). There was no obvious relationship between apelin and BMP 9 or BMP10 previously measured in these patients. Within the cirrhotic group, there was no significant correlation between apelin levels and disease severity scores, age, sex, or treatment with ß-blockers. CONCLUSIONS: Apelin was significantly reduced in plasma of patients with both early (fibrosis) and late-stage (cirrhosis) liver disease. Fibrosis is more easily reversible and may represent a potential target for new therapeutic interventions. However, it remains unclear whether apelin signalling is detrimental in liver disease or is beneficial and therefore, whether an apelin antagonist or agonist have clinical use.
Assuntos
Apelina/sangue , Proteínas Morfogenéticas Ósseas/sangue , Fibrose/sangue , Fator 2 de Diferenciação de Crescimento/sangue , Cirrose Hepática/sangue , Adulto , Idoso , Feminino , Fibrose/patologia , Humanos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
The embryonic endocardium is essential for early heart development as it functions to induce trabecular myocardium, the first heart tissue to form, and is the source of the cells that make up the valves and a portion of the coronary vasculature. With this potential, human endocardial cells could provide unique therapeutic opportunities that include engineering biological valves and cell-based therapy strategies to replace coronary vasculature in damaged hearts. To access human endocardial cells, we generated a human pluripotent stem cell (hPSC)-derived endothelial population that displays many characteristics of endocardium, including expression of the cohort of genes that identifies this lineage in vivo, the capacity to induce a trabecular fate in immature cardiomyocytes in vitro, and the ability to undergo an endothelial-to-mesenchymal transition. Analyses of the signaling pathways required for development of the hPSC-derived endocardial cells identified a novel role for BMP10 in the specification of this lineage from cardiovascular mesoderm.