Abstract:
BACKGROUND:Heart failure is a growing cause of morbidity and mortality worldwide. Transforming growth factor beta (TGF-β1) promotes cardiac fibrosis, but also activates counterregulatory pathways that serve to regulate TGF-β1 activity in heart failure. Bone morphogenetic protein 9 (BMP9) is a member of the TGFβ family of cytokines and signals via the downstream effector protein Smad1. Endoglin is a TGFβ coreceptor that promotes TGF-β1 signaling via Smad3 and binds BMP9 with high affinity. We hypothesized that BMP9 limits cardiac fibrosis by activating Smad1 and attenuating Smad3, and, furthermore, that neutralizing endoglin activity promotes BMP9 activity. METHODS:We examined BMP9 expression and signaling in human cardiac fibroblasts and human subjects with heart failure. We used the transverse aortic constriction-induced model of heart failure to evaluate the functional effect of BMP9 signaling on cardiac remodeling. RESULTS:BMP9 expression is increased in the circulation and left ventricle (LV) of human subjects with heart failure and is expressed by cardiac fibroblasts. Next, we observed that BMP9 attenuates type I collagen synthesis in human cardiac fibroblasts using recombinant human BMP9 and a small interfering RNA approach. In BMP9-/- mice subjected to transverse aortic constriction, loss of BMP9 activity promotes cardiac fibrosis, impairs LV function, and increases LV levels of phosphorylated Smad3 (pSmad3), not pSmad1. In contrast, treatment of wild-type mice subjected to transverse aortic constriction with recombinant BMP9 limits progression of cardiac fibrosis, improves LV function, enhances myocardial capillary density, and increases LV levels of pSmad1, not pSmad3 in comparison with vehicle-treated controls. Because endoglin binds BMP9 with high affinity, we explored the effect of reduced endoglin activity on BMP9 activity. Neutralizing endoglin activity in human cardiac fibroblasts or in wild-type mice subjected to transverse aortic constriction-induced heart failure limits collagen production, increases BMP9 protein levels, and increases levels of pSmad1, not pSmad3. CONCLUSIONS:Our results identify a novel functional role for BMP9 as an endogenous inhibitor of cardiac fibrosis attributable to LV pressure overload and further show that treatment with either recombinant BMP9 or disruption of endoglin activity promotes BMP9 activity and limits cardiac fibrosis in heart failure, thereby providing potentially novel therapeutic approaches for patients with heart failure.
journal_name
Circulationjournal_title
Circulationauthors
Morine KJ,Qiao X,York S,Natov PS,Paruchuri V,Zhang Y,Aronovitz MJ,Karas RH,Kapur NKdoi
10.1161/CIRCULATIONAHA.117.031635subject
Has Abstractpub_date
2018-07-31 00:00:00pages
513-526issue
5eissn
0009-7322issn
1524-4539pii
CIRCULATIONAHA.117.031635journal_volume
138pub_type
杂志文章相关文献
CIRCULATION文献大全abstract:BACKGROUND:Arterial relaxation is largely regulated by endothelial nitric oxide (NO). Its diminished activity has been associated with incipient atherosclerosis. We investigated the endothelium-dependent relaxation of aorta in apolipoprotein E-knockout (apoE-KO) mice exposed to single or repeated Chlamydia pneumoniae i...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.102.9.1039
更新日期:2000-08-29 00:00:00
abstract:BACKGROUND:This study sought to evaluate the clinical impact of angiographic complete revascularization (CR) after drug-eluting stent implantation or coronary artery bypass graft surgery for multivessel coronary disease. METHODS AND RESULTS:A total of 1914 consecutive patients with multivessel coronary disease undergo...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/CIRCULATIONAHA.110.005041
更新日期:2011-05-31 00:00:00
abstract:BACKGROUND:Apoptosis contributes to cell loss after ischemia/reperfusion injury in the heart. This study describes the time course and level of apoptosis in different cell types in the intact heart during ischemia/reperfusion injury. METHODS AND RESULTS:Isolated Langendorff-perfused rat hearts were subjected to perfus...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.104.3.253
更新日期:2001-07-17 00:00:00
abstract::Endocardial catheter mapping was performed in 15 patients in sinus rhythm who had no evidence of structural heart disease and normal left ventricles. Mapping was performed with the use of 10 mm interelectrode distance from various left ventricular endocardial sites. In 10 patients a quantitative analysis of electrogra...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.70.1.37
更新日期:1984-07-01 00:00:00
abstract:BACKGROUND:Plasma C-reactive protein (CRP) concentrations are increased in obese and/or hyperinsulinemic individuals. The goal of this study was to determine if the relation between insulin resistance and CRP was independent of obesity. METHODS AND RESULTS:Plasma CRP concentrations were measured before and after 3 mon...
journal_title:Circulation
pub_type: 临床试验,杂志文章
doi:10.1161/01.cir.0000041046.32962.86
更新日期:2002-12-03 00:00:00
abstract:BACKGROUND:The safety and efficacy of percutaneous coronary intervention of de novo lesions in unprotected left main coronary arteries remains an unresolved issue. METHODS AND RESULTS:We analyzed 67 consecutive patients treated with the following devices: 39 with stents, 12 with rotational atherectomy plus stents, 13 ...
journal_title:Circulation
pub_type: 临床试验,杂志文章
doi:10.1161/01.cir.0000024983.34728.5d
更新日期:2002-08-06 00:00:00
abstract:BACKGROUND:Optimal management of acute pulmonary embolism (PE) requires medical expertise, diagnostic testing, and therapies that may not be available consistently throughout the entire week. We sought to assess whether associations exist between weekday or weekend admission and mortality and length of hospital stay fo...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/CIRCULATIONAHA.108.824292
更新日期:2009-02-24 00:00:00
abstract:BACKGROUND:The mechanism of ECG changes and arrhythmogenesis in Brugada syndrome (BS) patients is unknown. METHODS AND RESULTS:A BS patient without clinically detected cardiac structural abnormalities underwent cardiac transplantation for intolerable numbers of implantable cardioverter/defibrillator discharges. The pa...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/CIRCULATIONAHA.105.532614
更新日期:2005-11-01 00:00:00
abstract:BACKGROUND:There is no consensus on how, when, or at what intensity exercise should be performed after heart transplantation (HTx). We have recently shown that high-intensity interval training (HIT) is safe, well tolerated, and efficacious in the maintenance state after HTx, but studies have not investigated HIT effect...
journal_title:Circulation
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1161/CIRCULATIONAHA.118.036747
更新日期:2019-05-07 00:00:00
abstract:BACKGROUND:The rate-corrected QT interval (QTc) is heritable, and the discovery of quantitative trait loci that influence the QTc would be an important step in identifying the genes responsible for life-threatening arrhythmias in the general population. We studied 66 pairs of unselected normal dizygotic (DZ) twin subje...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.99.24.3161
更新日期:1999-06-22 00:00:00
abstract:BACKGROUND:Associations of obesity with incidence of heart failure have been observed, but the causality is uncertain. We hypothesized that gastric bypass surgery leads to a lower incidence of heart failure compared with intensive lifestyle modification in obese people. METHODS:We included obese people without previou...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/CIRCULATIONAHA.116.025629
更新日期:2017-04-25 00:00:00
abstract::Cardiac hypertrophy is the physiological adaptation of the heart to chronic mechanical overload. Cardiac failure indicates the limits of the process. Cardiac hypertrophy is only one example of biological adaptation and results from the induction of several changes in gene expression, mostly of the fetal type, includin...
journal_title:Circulation
pub_type: 杂志文章,评审
doi:
更新日期:1993-05-01 00:00:00
abstract::The widespread use of exercise testing for the detection of myocardial ischemia in patients suspected of having coronary artery disease led to the detection of ischemic changes in many subjects who subsequently were found to have angiographically normal epicardial vessels--the false positive response. Such a result is...
journal_title:Circulation
pub_type: 杂志文章
doi:
更新日期:1991-05-01 00:00:00
abstract:BACKGROUND:Predictors of antiplatelet therapy discontinuation (ATD) during the first year after drug-eluting stent implantation are poorly known. METHODS AND RESULTS:This was a prospective study with 3-, 6-, 9-, and 12-month follow-up of patients receiving at least 1 drug-eluting stent between January and April 2008 i...
journal_title:Circulation
pub_type: 临床试验,杂志文章
doi:10.1161/CIRCULATIONAHA.110.938290
更新日期:2010-09-07 00:00:00
abstract::We studied the inferior vena cava (IVC) as an index of right-heart function in 111 patients. A two-dimensional echocardiographic sector was used to visualize the IVC, and its M-mode cursor was used to generate a time-motion record of the IVC size and pulsation. Normal subjects had a small presystolic A wave (less than...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.64.5.1018
更新日期:1981-11-01 00:00:00
abstract:BACKGROUND:It is not known whether progression of aortic arch (AA) atheroma is associated with vascular events in patients with stroke or transient ischemic attack (TIA). METHODS AND RESULTS:AA atheroma was detected on baseline transesophageal echocardiogram in 167 consecutive patients who had prevalent stroke or TIA....
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/CIRCULATIONAHA.106.671727
更新日期:2007-08-21 00:00:00
abstract::The rapid development of new drugs, therapies, and devices has created a dramatic increase in the number of trials needed to properly evaluate them. The majority of patients treated today, many of whom could be eligible for participation in these studies, are seen in community hospitals and medical practices that are ...
journal_title:Circulation
pub_type: 杂志文章,评审
doi:10.1161/01.CIR.0000128702.16441.75
更新日期:2004-06-01 00:00:00
abstract:BACKGROUND:Two phase III trials of enoxaparin for unstable angina/non-Q-wave myocardial infarction have shown it to be superior to unfractionated heparin for preventing a composite of death and cardiac ischemic events. A prospectively planned meta-analysis was performed to provide a more precise estimate of the effects...
journal_title:Circulation
pub_type: 临床试验,杂志文章,meta分析,多中心研究
doi:10.1161/01.cir.100.15.1602
更新日期:1999-10-12 00:00:00
abstract:BACKGROUND:Failure to differentiate supraventricular from ventricular arrhythmias is the most frequent cause of inappropriate implantable cardioverter-defibrillator therapies. Although a sudden-onset criterion is available to differentiate sustained monomorphic ventricular tachycardias (SMVTs) and sinus tachycardias (S...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.98.7.671
更新日期:1998-08-18 00:00:00
abstract:BACKGROUND:The mechanisms by which replacement hormones may reduce the risk of coronary heart disease are not fully understood. Of specific interest is a potential effect of replacement hormones on plasma fibrinolytic activity, a putative determinant of thrombotic events. METHODS AND RESULTS:We investigated the relati...
journal_title:Circulation
pub_type: 杂志文章,多中心研究
doi:10.1161/01.cir.93.11.1970
更新日期:1996-06-01 00:00:00
abstract:BACKGROUND:Unstable atherosclerotic lesions typically have an abundant inflammatory cell infiltrate, including activated T cells, macrophages, and mast cells, which may decrease plaque stability. The pathophysiology of inflammatory cell recruitment and activation in the human atheroma is incompletely described. METHOD...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.102.18.2185
更新日期:2000-10-31 00:00:00
abstract:BACKGROUND:In large mammals and humans, the contribution of IKs to ventricular repolarization is still incompletely understood. METHODS AND RESULTS:In vivo and cellular electrophysiological experiments were conducted to study IKs in canine ventricular repolarization. In conscious dogs, administration of the selective ...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.CIR.0000068344.54010.B3
更新日期:2003-06-03 00:00:00
abstract:BACKGROUND:This multicenter trial was conducted to determine the efficacy and safety of pimobendan, an inotropic agent with calcium-sensitizing properties and activity as a phosphodiesterase inhibitor, in patients with heart failure. METHODS AND RESULTS:One hundred ninety-eight ambulatory patients with symptoms of mod...
journal_title:Circulation
pub_type: 临床试验,杂志文章,多中心研究,随机对照试验
doi:10.1161/01.cir.85.3.942
更新日期:1992-03-01 00:00:00
abstract::Until the 1990s, venous thromboembolism (VTE) was viewed primarily as a complication of hospitalization for major surgery (or associated with the late stage of terminal illness). However, recent trials in patients hospitalized with a wide variety of acute medical illnesses have demonstrated a risk of VTE in medical pa...
journal_title:Circulation
pub_type: 杂志文章,评审
doi:10.1161/01.CIR.0000078469.07362.E6
更新日期:2003-06-17 00:00:00
abstract::Using a mechanical sector-scanner, two-dimensional echocardiograms were obtained from 28 normal subjects, 15 patients with tetralogy of Fallot, 11 patients with complete transposition of the great arteries and six patients with double outlet right ventricle. The image obtained perpendicular to the long axis of the lef...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.56.2.267
更新日期:1977-08-01 00:00:00
abstract:BACKGROUND:In the past few years, although significant efforts have been made to assess flow distribution during retrograde cerebral perfusion with microspheres, dye, or hydrogen clearance, flow distribution in real time is still undefined. We used MR perfusion imaging to monitor flow distribution in the brain during a...
journal_title:Circulation
pub_type: 杂志文章
doi:
更新日期:1998-11-10 00:00:00
abstract:BACKGROUND:Pulmonary hypertension is a fatal disease characterized by vasoconstriction and vascular remodeling. Loss of endothelial nitric oxide bioavailability is implicated in pulmonary hypertension pathogenesis. Recent evidence suggests that the cofactor tetrahydrobiopterin (BH4) is an important regulator of nitric ...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.CIR.0000162470.26840.89
更新日期:2005-04-26 00:00:00
abstract::The purpose of this study was to identify preoperative and intraoperative variables predictive of left ventricular dysfunction 6 months after aortic valve replacement. Patients were considered to have postoperative left ventricular dysfunction if the end-diastolic-volume index was greater than or equal to 101 ml/m2 or...
journal_title:Circulation
pub_type: 临床试验,杂志文章,多中心研究
doi:
更新日期:1989-09-01 00:00:00
abstract:BACKGROUND:ε protein kinase C (εPKC) is involved in vascular smooth muscle cell (VSMC) activation, but little is known about its function in vascular pathology. We aimed at assessing the role of εPKC in the development of restenosis. METHODS AND RESULTS:Rat models of aortic balloon injury with or without subsequent st...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/CIRCULATIONAHA.109.927640
更新日期:2010-09-14 00:00:00
abstract:BACKGROUND:The management of asymptomatic severe mitral regurgitation remains controversial. The aim of this study was to evaluate the outcome of a watchful waiting strategy in which patients are referred to surgery when symptoms occur or when asymptomatic patients develop left ventricular (LV) enlargement, LV dysfunct...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/CIRCULATIONAHA.105.599175
更新日期:2006-05-09 00:00:00