Multi-Biomarker Points and Outcomes in Patients Hospitalized for Heart Failure: Insights From the China PEACE Prospective Heart Failure Study.

Objective: To quantitatively characterize the pattern of systemic impairment reflected by conventional biomarkers and assess how it relates to clinical outcomes and quality of life among patients hospitalized for heart failure (HF). Methods: Patients hospitalized for HF from 52 hospitals in China were enrolled between 2016 and 2018. They were divided into developing and validating cohorts; the developing cohort was used for calculating the weights of biomarkers and constructing the multi-biomarker panel, while the validating one was used for evaluating the relationship between multi-biomarker points and outcomes. In total, five conventional biomarkers reflecting various pathophysiological processes were included in the panel: N-terminal pro-B type natriuretic peptide, high-sensitivity troponin T, hemoglobin, albumin, and creatinine. The weights of the biomarkers were defined based on their relationship with cardiovascular death, and each patient had a multi-biomarker point ranging from 0 to 12. The primary clinical outcome was cardiovascular death, and the other clinical outcomes included rehospitalization for HF, all-cause death, and all-cause rehospitalization in 1-year. The quality of life was measured using Kansas City Cardiovascular Questionnaire. Multi-variable Cox proportional hazard models were used to assess the risks of clinical outcomes, and generalized linear models were used to evaluate the quality of life. Results: In total, 4,693 patients hospitalized for HF were included in this analysis; the median (interquartile range, IQR) age was 67 (57-75) years old and 1,763 (37.6%) were female. The median multi-biomarker point was 5 (IQR, 2-6). There were 18.0% of patients in the low point group (<2), 29.4% in the mid-low point group (2-4), 27.8% in the mid-high point group (5-6), and 24.7% in the high point group (>6). Compared with those in the low point group, the patients in the high point group had a significantly excess risk of cardiovascular death (adjusted hazard ratio: 5.69, 95% CI, 3.33-9.70). Furthermore, patients with higher points were also more prone to worse quality of life. Conclusion: Systemic impairment reflected by abnormal conventional biomarker values was common amongst patients hospitalized for HF and had substantially cumulative adverse influence on clinical outcomes and quality of life.

Discharge heart rate and 1-year clinical outcomes in heart failure patients with atrial fibrillation.

BACKGROUND: The association between heart rate and 1-year clinical outcomes in heart failure (HF) patients with atrial fibrillation (AF), and whether this association depends on left ventricular ejection fraction (LVEF), are unclear. We investigated the relationship between discharge heart rate and 1-year clinical outcomes after discharge among hospitalized HF patients with AF, and further explored this association that differ by LVEF level. METHODS: In this analysis, we enrolled 1760 hospitalized HF patients with AF from the China Patient-centered Evaluative Assessment of Cardiac Events Prospective Heart Failure study from August 2016 to May 2018. Patients were categorized into three groups with low (<65 beats per minute [bpm]), moderate (65-85 bpm), and high (≥86 bpm) heart rate measured at discharge. Cox proportional hazard models were employed to explore the association between heart rate and 1-year primary outcome, which was defined as a composite outcome of all-cause death and HF rehospitalization. RESULTS: Among 1760 patients, 723 (41.1%) were women, the median age was 69 (interquartile range [IQR]: 60-77) years, median discharge heart rate was 75 (IQR: 69-84) bpm, and 934 (53.1%) had an LVEF <50%. During 1-year follow-up, a total of 792 (45.0%) individuals died or had at least one HF hospitalization. After adjusting for demographic characteristics, smoking status, medical history, anthropometric characteristics, and medications used at discharge, the groups with low (hazard ratio [HR]: 1.32, 95% confidence interval [CI]: 1.05-1.68, P = 0.020) and high (HR: 1.34, 95% CI: 1.07-1.67, P = 0.009) heart rate were associated with a higher risk of 1-year primary outcome compared with the moderate group. A significant interaction between discharge heart rate and LVEF for the primary outcome was observed (P for interaction was 0.045). Among the patients with LVEF ≥50%, only those with high heart rate were associated with a higher risk of primary outcome compared with the group with moderate heart rate (HR: 1.38, 95% CI: 1.01-1.89, P = 0.046), whereas there was no difference between the groups with low and moderate heart rate. Among the patients with LVEF <50%, only those with low heart rate were associated with a higher risk of primary outcome compared with the group with moderate heart rate (HR: 1.46, 95% CI: 1.09-1.96, P = 0.012), whereas there was no difference between the groups with high and moderate heart rate. CONCLUSIONS: Among the overall HF patients with AF, both low (<65 bpm) and high (≥86 bpm) heart rates were associated with poorer outcomes as compared with moderate (65-85 bpm) heart rate. Among patients with LVEF ≥50%, only a high heart rate was associated with higher risk; while among those with LVEF <50%, only a low heart rate was associated with higher risk as compared with the group with moderate heart rate. TRAIL REGISTRATION: Clinicaltrials.gov; NCT02878811.

Characteristics, interventions and outcomes of patients with valvular heart disease hospitalised in China: a cross-sectional study.

OBJECTIVES: Little is known about contemporary characteristics and management of valvular heart disease (VHD) in China. This study aimed to examine the clinical characteristics, aetiology and type of VHD, interventions and in-hospital outcomes of patients with VHD hospitalised in China. METHODS: We used a two-stage random sampling design to create a nationally representative sample of patients with VHD hospitalised in 2015 in China and included adult patients with mild, moderate or severe VHD. We abstracted data from medical records, including echocardiogram reports, on patient characteristics, aetiology, type and severity of VHD, interventions and in-hospital outcomes. We weighted our findings to estimate nationally representative hospitalisations. We performed multivariable logistic regression analysis to identify factors associated with valve intervention. RESULTS: In 2015, 38 841 patients with VHD were hospitalised in 188 randomly sampled hospitals, representing 662 384 inpatients with VHD in China. We sampled 9363 patients, mean age 68.7 years (95% CI 42.2 to 95.2) and 46.8% (95% CI 45.8% to 47.8%) male, with an echocardiogram. Degenerative origin was the predominant aetiology overall (33.3%, 95% CI 32.3% to 34.3%), while rheumatic origin was the most frequent aetiology among patients with VHD as the primary diagnosis (37.4%, 95% CI 35.9% to 38.8%). Rheumatic origin was also the most common aetiology among patients with moderate or severe VHD (27.3%, 95% CI 25.6% to 29.0% and 33.6%, 95% CI 31.9% to 35.2%, respectively). The most common VHD was mitral regurgitation (79.1%, 95% CI 78.2% to 79.9%), followed by tricuspid regurgitation (77.4%, 95% CI 76.5% to 78.2%). Among patients with a primary diagnosis of severe VHD who were admitted to facilities capable of valve intervention, 35.6% (95% CI 33.1% to 38.1%) underwent valve intervention during the hospitalisation. The likelihood of intervention decreased significantly among patients with higher operative risk. CONCLUSIONS: Among patients with VHD hospitalised in China, the predominant aetiology was degenerative in origin; among patients with moderate or severe VHD, rheumatic origin was the most common aetiology. Targeted strategies and policies should be promoted to address degenerative VHD. Patients with severe VHD may be undertreated, particularly those with high operative risk.

Beta-blockers and 1-year clinical outcomes in hospitalized heart failure patients with atrial fibrillation.

OBJECTIVE: To assess the association between beta-blockers and 1-year clinical outcomes in heart failure (HF) patients with atrial fibrillation (AF), and further explore this association that differs by left ventricular ejection fraction (LVEF) level. METHODS: We enrolled hospitalized HF patients with AF from China Patient-centered Evaluative Assessment of Cardiac Events Prospective Heart Failure Study. COX proportional hazard regression models were employed to calculate hazard ratio of beta-blockers. The primary outcome was all-cause death. RESULTS: Among 1762 HF patients with AF (756 women [41.4%]), 1041 (56%) received beta-blockers at discharge and 1272 (72.2%) had an LVEF > 40%. During one year follow up, all-cause death occurred in 305 (17.3%), cardiovascular death occurred in 203 patients (11.5%), and rehospitalizations for HF occurred in 622 patients (35.2%). After adjusting for demographic characteristics, social economic status, smoking status, medical history, anthropometric characteristics, and medications used at discharge, the use of beta-blockers at discharge was not associated with all-cause death [hazard ratio (HR): 0.86; 95% Confidence Interval (CI): 0.65-1.12; P = 0.256], cardiovascular death (HR: 0.76, 95% CI: 0.52-1.11; P = 0.160), or the composite outcome of all-cause death and HF rehospitalization (HR: 0.97, 95% CI: 0.82-1.14; P = 0.687) in the entire cohort. There were no significant interactions between use of beta-blockers at discharge and LVEF with respect to all-cause death, cardiovascular death, or composite outcome. In the adjusted models, the use of beta-blockers at discharge was not associated with all-cause death, cardiovascular death, or composite outcome across the different levels of LVEF: reduced (< 40%), mid-range (40%-49%), or preserved LVEF (≥ 50%). CONCLUSION: Among HF patients with AF, the use of beta-blockers at discharge was not associated with 1-year clinical outcomes, regardless of LVEF.

Health Status Predicts Short- and Long-Term Risk of Composite Clinical Outcomes in Acute Heart Failure.

OBJECTIVES: This study aims to examine the association between the Kansas City Cardiomyopathy Questionnaire (KCCQ)-12 score and the 30-day and 1-year rates of composite events of cardiovascular death and heart failure (HF) rehospitalization in patients with acute HF. BACKGROUND: Few studies reported the prognostic effects of KCCQ in acute HF. METHODS: This study prospectively enrolled adult patients hospitalized for HF from 52 hospitals in China and collected the KCCQ-12 score within 48 hour of index admission. The study used multivariable Cox regression to examine the association between KCCQ-12 score and 30-day and 1-year composite events and was further stratified by new-onset HF and acutely decompensated chronic heart failure (ADCHF). Subgroup analyses were performed to explore the potential heterogeneity. The study evaluated the incremental prognostic value of KCCQ-12 score over N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and established risk scores by C-statistics, net reclassification improvement, and integrated discrimination improvement. RESULTS: Among 4,898 patients, 29.4% had new-onset HF. After adjustment, each 10-point decrease in the KCCQ-12 score was associated with a 13% increase in 30-day risk and a 7% increase in 1-year risk. The associations were consistent regardless of new-onset HF or ADCHF, age, sex, left ventricular ejection fraction, New York Heart Association functional class, NT-proBNP level, comorbidities, and renal function. Adding KCCQ-12 score to NT-proBNP and established risk scores significantly improved prognostic capabilities measured by C-statistics, net reclassification improvement, and integrated discrimination improvement. CONCLUSIONS: In acute HF, a poor KCCQ-12 score predicted short- and long-term risks of cardiovascular death and HF rehospitalization. KCCQ-12 could serve as a convenient tool for rapid initial risk stratification and provide additional prognostic value over NT-proBNP and established risk scores.

Highly Sensitive and Selective Photoelectrochemical Aptasensors for Cancer Biomarkers Based on MoS2/Au/GaN Photoelectrodes.

An Au/GaN photoelectrode was prepared by sputtering 30 nm thick Au film on the surface of n-type gallium nitride (GaN). When the electrode contacts with multilayered molybdenum disulfide (MoS2), photogenerated electrons and photogenerated holes transfer to MoS2 because of the band gap matching of MoS2 and GaN. The presence of Au promotes charge transfer and results in a greater recombination of electrons and holes; by this means, a more significant suppression of photocurrent can be detected. This characteristic has been coupled with the high selectivity of an aptamer and applied to develop a novel photoelectrochemical aptasensor for cancer biomarkers (alpha-fetoprotein (AFP) as a model). The aptamer of AFP was modified on the surface of the Au/GaN photoelectrode by Au-S bonds, which can bind to the target protein with high selectivity. Then, the transfer process of the charge carriers of GaN to MoS2 can be blocked by the target protein so that the suppression of photocurrent is reduced. The difference of the photocurrent in the presence and absence of AFP (ΔI) showed a linear relationship with AFP concentration that ranged from 1.0-150 ng/mL (R2 = 0.9995), and the detection limit was 0.3 ng/mL. The standard addition recovery rates ranged from 85.2 to 91.7%. The method possessed good sensitivity and high selectivity for AFP detection. The developed biosensor can be modified to detect other cancer biomarkers by simply replacing the aptamer used.

Risk gene identification and support vector machine learning to construct an early diagnosis model of myocardial infarction.

The present study aimed to identify genes associated with increased risk of myocardial infarction (MI) and construct an early diagnosis model based on support vector machine (SVM) learning. The gene expression profile data of GSE34198, containing 97 human blood samples including 49 patients with MI and 48 healthy individuals, were obtained from the Gene Expression Omnibus database. Differentially expressed gene (DEG) screening, DEG enrichment analysis, protein­protein interaction (PPI) network investigation and clustering analysis were performed. The feature genes were identified using the neighboring score algorithm. Furthermore, a recursive feature elimination (RFE) algorithm was employed to screen risk factors among feature genes. The SVM prediction model was constructed and validated using the dataset GSE61144. A total of 1,207 DEGs (724 downregulated, 483 upregulated) between the two groups were identified. PPI analysis investigated 1,083 DEGs and 46,363 edges. In total, 87 genes were selected as candidate genes, and were primarily enriched in functions including 'G­protein coupled receptor signaling' or pathways such as 'focal adhesion'. Furthermore, 15 genes with a high RFE score were selected to construct an SVM prediction model. The model's average accuracy was 86%. Data set verification showed that the predictive precision reached 0.92. High expression of the genes vascular endothelial growth factor A, A­kinase anchoring protein 12 and olfactory receptor 8D2 were potential risk factors for MI. The SVM early diagnosis model constructed by candidate genes could not only predict early MI, but also provide risk probability according to the severity of MI.

Highly Sensitive and Selective Photoelectrochemical Aptasensor for Cancer Biomarker CA125 Based on AuNPs/GaN Schottky Junction.

A gold nanoparticle (AuNPs)/gallium nitride (GaN) Schottky junction was fabricated by growing AuNPs in situ on the surface of GaN and then etched by H2O2 to appropriate diameter. The photogenerated electrons of GaN can be captured and transferred by the AuNPs to increase the migration efficiency, and the electron-hole pairs were separated, which results in the enhancement of the photoelectric performance of the system. The Fermi energy level of AuNPs and the charge transfer efficiency of the AuNPs/GaN can be adjusted by controlling the size of the AuNPs. Then the AuNPs/GaN Schottky photoelectrode had been applied to develop a novel photoelectrochemical (PEC) aptasensor for the epithelial ovarian cancer marker-CA125 detection. The DNA aptamer of CA125 was modified on the surface of the AuNPs via Au-S bonds. The aptamer can bind with the target with high selectivity, and the photoelectron transfer process of the system can be blocked by the protein, which results in the decrease of the photocurrent of the system. The ratio of photocurrent before and after incubation with CA125 (I1/I0) has a linear with the concentration of CA125 in the range of 1-100 U/mL with a detection limit of 0.3 U/mL. The standard addition recovery rates were between 86.01% and 90.09%. This method showed good sensitivity, selectivity, and reliability in detecting CA125 in serum.

Age­related changes in mineralocorticoid receptors in rat hearts.

Age-related alterations in the renin-angiotensin-aldosterone system (RAAS) have been reported in the cardiovascular system; however, the detailed mechanism of the RAAS component mineralocorticoid receptors (MR) has not been elucidated. The present study aimed to investigate the associations between MR and cardiac aging in rats, as well as the regulatory effects of oxidative stress and mitochondrial abnormalities in the aging process. MR expression in the hearts of male Sprague­Dawley rats aged 3 months (young rats) and 24 months (old rats) was evaluated in vivo. In addition, in vitro, H9C2 cells were treated with a specific MR antagonist, eplerenone, in order to investigate the molecular mechanism underlying the inhibition of myocyte aging process. The results demonstrated that MR expression was significantly higher in 24­month­old rat hearts compared with in 3­month­old rat hearts. These changes were accompanied by increased p53 expression, decreased peroxisome proliferator­activated receptor γ coactivator­1α expression, decreased mitochondrial renewal as assessed by electron microscopy, increased oxidative stress and decreased superoxide dismutase. In vitro, selective antagonism of MR partially blocked H2O2­induced myocardial aging as assessed by p16, p21 and p53 expression levels and excessive reactive oxygen species (ROS) accumulation. These results indicated that increased MR expression may drive age­related cardiac dysfunction via mitochondrial damage, increased ROS accumulation and an imbalanced redox state.

Human kallikrein overexpression alleviates cardiac aging by alternatively regulating macrophage polarization in aged rats.

Cardiac aging is characterized by myocardial hypertrophy, fibrosis, and diastolic dysfunction. Human kallikrein (hKLK1) protects against fibrosis in various pathogenic states. However, the effects of hKLK1 overexpression on cardiac aging-related fibrosis and the underlying mechanisms remain unknown. Moreover, the role of hKLK1 in regulating macrophage function leading to cardiac fibrosis has not been investigated. Thus, in this study, we determined the effects of hKLK1 on cardiac aging and explored the mechanisms through which hKLK1 regulated aging-related fibrosis. Echocardiographic measurements showed that aging caused significant alternations in cardiac morphology, hypertrophy, and fibrosis in rats, and hKLK1 overexpression protected against aging-induced cardiac dysfunction. Compared with wild-type hearts, the hKLK1 transgene decreased the expression of monocyte chemoattractant protein 1 and suppressed mitochondrial dysfunction and excess oxidative stress, leading to decreased recruitment and retention of alternatively activated (M2) macrophages and reduced secretion of profibrotic cytokines mediated by the TGF-ß1-Smad3 signaling pathway in hearts of aging rats. Furthermore, these cardioprotective effects of hKLK1 overexpression were associated with the Janus kinase-signal transducer and activator of transcription 3 signaling pathway. H2O2-induced senescence promoted the differentiation of RAW264.7 cells into M2-type cells induced by IL-4 treatment. Bradykinin treatment relieved the migratory capacity of macrophages induced by H2O2. Thus, hKLK1 overexpression reduced cardiac fibrosis and improved aging-related cardiac dysfunction through reduced shift of macrophages to M2 macrophages, indicating that hKLK1 may alleviate aging-related cardiac dysfunction.-Hu, D., Dong, R., Yang, Y., Chen, Z., Tang, Y., Fu, M., Wang, D. W., Xu, X., Tu, L. Human kallikrein overexpression alleviates cardiac aging by alternatively regulating macrophage polarization in aged rats.

Endothelium-specific CYP2J2 overexpression attenuates age-related insulin resistance.

Ample evidences demonstrate that cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids (EETs) exert diverse biological activities, which include potent vasodilatory, anti-inflammatory, and cardiovascular protective effects. In this study, we investigated the effects of endothelium-specific CYP2J2 overexpression on age-related insulin resistance and metabolic dysfunction. Endothelium-specific targeting of the human CYP epoxygenase, CYP2J2, transgenic mice (Tie2-CYP2J2-Tr mice) was utilized. The effects of endothelium-specific CYP2J2 overexpression on aging-associated obesity, inflammation, and peripheral insulin resistance were evaluated by assessing metabolic parameters in young (3 months old) and aged (16 months old) adult male Tie2-CYP2J2-Tr mice. Decreased insulin sensitivity and attenuated insulin signaling in aged skeletal muscle, adipose tissue, and liver were observed in aged adult male mice, and moreover, these effects were partly inhibited in 16-month-old CYP2J2-Tr mice. In addition, CYP2J2 overexpression-mediated insulin sensitization in aged mice was associated with the amelioration of inflammatory state. Notably, the aging-associated increases in fat mass and adipocyte size were only observed in 16-month-old wild-type mice, and CYP2J2 overexpression markedly prevented the increase in fat mass and adipocyte size in aged Tie2-CYP2J2-Tr mice, which was associated with increased energy expenditure and decreased lipogenic genes expression. Furthermore, these antiaging phenotypes of Tie2-CYP2J2-Tr mice were also associated with increased muscle blood flow, enhanced active-phase locomotor activity, and improved mitochondrial dysfunction in skeletal muscle. Collectively, our findings indicated that endothelium-specific CYP2J2 overexpression alleviated age-related insulin resistance and metabolic dysfunction, which highlighted CYP epoxygenase-EET system as a potential target for combating aging-related metabolic disorders.

EETs reduces LPS-induced hyperpermeability by targeting GRP78 mediated Src activation and subsequent Rho/ROCK signaling pathway.

Integrity of endothelial barrier is a determinant of the prognosis in the acute lung injury caused by sepsis. The epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid, exhibit protective effects in various pathogenic states, however, whether EETs play a role in endothelial barrier enhancement and the involved mechanisms remain to be investigated. Here, we show that increased EETs level by endothelial specific cytochrome P450 epoxygenase 2J2 over-expression and soluble epoxide hydrolase (sEH) inhibitor TPPU reduced lipopolysaccharide-induced endothelial hyper-permeability in vivo, accompanied by improved survival of septic mice. In addition, sEH inhibitor AUDA and 11,12-EET also decreased endothelial hyper-permeability in the in-vitro study. Importantly, the relative mechanisms were associated with reduced GRP78-Src interaction and ROS production, and subsequently reduced RhoA/ROCK activation, and eventually decreased VE-cadherin and myosin light chain (MLC) phosphorylation. Thus CYP2J2-EETs is crucial for RhoA-dependent regulation of cytoskeletal architecture leading to reversible changes in vascular permeability, which may contribute to the development of new therapeutic approaches for pulmonary edema and other diseases caused by abnormal vascular permeability.

Liver Kinase B1/AMP-Activated Protein Kinase Pathway Activation Attenuated the Progression of Endotoxemia in the Diabetic Mice.

BACKGROUND/AIMS: Sepsis is a common disease that continues to increase in prevalence worldwide, and diabetes mellitus may make the situation worse. This study was designed to determine the role of Liver Kinase B1 (LKB1)/adenosine monophosphate-activated protein kinase (AMPK) signaling pathway in diabetic mice complicated with systemic endotoxemia. METHODS: The effects of LKB1/AMPK signaling pathway activation on endotoxemia were investigated in streptozotocin induced diabetic mice (STZ-mice) and db/db diabetic mice. Primary peritoneal macrophages and human umbilical vein endothelial cells (HUVECs) monolayers were simultaneously stimulated by both high glucose and LPS and used as a model to investigate the potential molecular mechanisms in vitro. RESULTS: After treatment with LPS, high glucose or both LPS and high glucose, phosphor-AMPK expression was decreased, and moreover, AMPK activation by metformin treatment alleviated the decrease in phosphor-AMPK expression in HUVECs and macrophages as well as in lung tissue. Furthermore, both LPS and high glucose co-treatment decreased LKB1 and phosphor-AMPK expression via enhanced oxidative stress response, and importantly, LKB1 overexpression mediated by adenovirus inhibited the decrease in phosphor-AMPK expression in macrophages and HUVECs. AMPK activation by metformin administration improved the survival of STZ-induced diabetic mice and db/db diabetic mice, which was associated with reduced lung endothelial hyperpermeability and systemic inflammatory response. Furthermore, the permeability of HUVECs monolayers induced by both high glucose and LPS stimulation was also alleviated by AMPK activation, which was partly via suppression of VE-cadherin phosphorylation. CONCLUSION: These data demonstrated that LKB1/AMPK signaling pathway activation improved the survival of diabetic mice complicated with endotoxemia. Thus, LKB1/AMPK signaling pathway may serve as a potentially useful therapeutic target for severe infection in diabetic patients.

Exogenous Bradykinin Inhibits Tissue Factor Induction and Deep Vein Thrombosis via Activating the eNOS/Phosphoinositide 3-Kinase/Akt Signaling Pathway.

BACKGROUND/AIMS: Bradykinin has been shown to exert a variety of protective effects against vascular injury, and to reduce the levels of several factors involved in the coagulation cascade. A key determinant of thrombin generation is tissue factor (TF). However, whether bradykinin can regulate TF expression remains to be investigated. METHODS: To study the effect of bradykinin on TF expression, we used Lipopolysaccharides (LPS) to induce TF expression in human umbilical vein endothelial cells and monocytes. Transcript levels were determined by RT-PCR, protein abundance by Western blotting. In the in vivo study, bradykinin and equal saline were intraperitoneally injected into mice for three days ahead of inferior cava vein ligation that we took to induce thrombus formation, after which bradykinin and saline were injected for another two days. Eventually, the mice were sacrificed and tissues were harvested for tests. RESULTS: Exogenous bradykinin markedly inhibited TF expression in mRNA and protein level induced by LPS in a dose-dependent manner. Moreover, the NO synthase antagonist L-NAME and PI3K inhibitor LY294002 dramatically abolished the inhibitory effects of bradykinin on tissue factor expression. PI3K/Akt signaling pathway activation induced by bradykinin administration reduced the activity of GSK-3ß and MAPK, and reduced NF-x03BA;B level in the nucleus, thereby inhibiting TF expression. Consistent with this, intraperitoneal injection of C57/BL6 mice with bradykinin also inhibited the thrombus formation induced by ligation of inferior vena cava. CONCLUSION: Bradykinin suppressed TF protein expression in human umbilical vein endothelial cells and monocytes in vitro; in line with this, it inhibits thrombus formation induced by ligation of inferior vena cava in vivo.