Lipopolysaccharide pretreatment increases protease-activated receptor-2 expression and monocyte chemoattractant protein-1 secretion in vascular endothelial cells.

BACKGROUND: This study investigated whether lipopolysaccharide (LPS) increase protease-activated receptor-2 (PAR-2) expression and enhance the association between PAR-2 expression and chemokine production in human vascular endothelial cells (ECs). METHODS: The morphology of ECs was observed through microphotography in cultured human umbilical vein ECs (EA. hy926 cells) treated with various LPS concentrations (0, 0.25, 0.5, 1, and 2 µg/mL) for 24 h, and cell viability was assessed using the MTT assay. Intracellular calcium imaging was performed to assess agonist (trypsin)-induced PAR-2 activity. Western blotting was used to explore the LPS-mediated signal transduction pathway and the expression of PAR-2 and adhesion molecule monocyte chemoattractant protein-1 (MCP-1) in ECs. RESULTS: Trypsin stimulation increased intracellular calcium release in ECs. The calcium influx was augmented in cells pretreated with a high LPS concentration (1 µg/mL). After 24 h treatment of LPS, no changes in ECs viability or morphology were observed. Western blotting revealed that LPS increased PAR-2 expression and enhanced trypsin-induced extracellular signal-regulated kinase (ERK)/p38 phosphorylation and MCP-1 secretion. However, pretreatment with selective ERK (PD98059), p38 mitogen-activated protein kinase (MAPK) (SB203580) inhibitors, and the selective PAR-2 antagonist (FSLLRY-NH2) blocked the effects of LPS-activated PAR-2 on MCP-1 secretion. CONCLUSIONS: Our findings provide the first evidence that the bacterial endotoxin LPS potentiates calcium mobilization and ERK/p38 MAPK pathway activation and leads to the secretion of the pro-inflammatory chemokine MCP-1 by inducing PAR-2 expression and its associated activity in vascular ECs. Therefore, PAR-2 exerts vascular inflammatory effects and plays an important role in bacterial infection-induced pathological responses.

Nicorandil Inhibits Cyclic Strain-Induced Interleukin-8 Expression in Human Umbilical Vein Endothelial Cells.

BACKGROUND: Nicorandil, a mitochondrial adenosine triphosphate-sensitive potassium (mitoKATP) channel opener, exerts protective effects on the cardiovascular system. This study examined the effect of nicorandil on cyclic strain-induced interleukin-8 (IL-8) expression in human umbilical vein endothelial cells (HUVECs). METHODS: Cultured HUVECs were exposed to cyclic strain in the presence or absence of nicorandil (1-10 µmol/l); we then analyzed IL-8 expression. We also assessed the effects of nicorandil on heme oxygenase-1 (HO-1) expression and cyclic strain-modulated IL-8 expression after HO-1 silencing in HUVECs. SUMMARY: HUVECs exposed to cyclic strain showed increased IL-8 messenger RNA expression and protein secretion. Nicorandil (1-10 µmol/l) inhibited cyclic strain-induced IL-8 expression, whereas 5-hydroxydecanoate (100 µmol/l), a selective inhibitor of the mitoKATP channel, completely reversed the inhibitory effects of nicorandil on cyclic strain-induced IL-8 expression. We demonstrated that nicorandil increased HO-1 expression in HUVECs. In addition, cobalt protoporphyrin (10 µmol/l), an inducer of HO-1 expression, mimicked the effects of nicorandil and inhibited IL-8 expression under cyclic strain, whereas zinc protoporphyrin IX (10 µmol/l), an inhibitor of HO-1 expression, antagonized the effect of nicorandil. HO-1 silencing significantly abrogated the inhibitory effects of nicorandil on cyclic strain-induced IL-8 expression, suggesting that HO-1 plays a role in the mechanism of action of nicorandil. KEY MESSAGES: This study is the first to report that nicorandil inhibits cyclic strain-induced IL-8 expression through the induction of HO-1 expression in HUVECs. This finding provides valuable new insight into the molecular pathways contributing to the vasoprotective effects of nicorandil.

Renal dysfunction and the risk of postoperative atrial fibrillation after cardiac surgery: role beyond the CHA2DS2-VASc score.

AIMS: To investigate whether renal dysfunction is a useful predictor of postoperative atrial fibrillation (POAF) after cardiac surgery. We also aimed to determine whether the addition of renal dysfunction into the scoring system could improve diagnostic accuracy of the CHA2DS2-VASc score to predict POAF. METHODS AND RESULTS: The study prospectively enrolled 350 consecutive patients who underwent cardiac surgery. Echocardiography was performed before cardiac surgery. Renal dysfunction was defined as estimated glomerular filtration rate < 60 mL min(-1) 1.73 m(-2). All patients were monitored with continuous electrocardiographic telemetry for the occurrence of POAF until the day of hospital dismissal. Postoperative atrial fibrillation occurred in 103 of 350 patients (29%). Patients with POAF was associated with longer intensive care unit stay compared with those without POAF (3.7 ± 2.2 vs. 3.1 ± 1.4 days, P = 0.002). Both the CHA2DS2-VASc score and renal dysfunction were independent predictors of POAF in multivariate analysis. Renal dysfunction can further stratify patients with a CHA2DS2-VASc score of 0 or 1 into two groups with different POAF rates (3.1% vs. 68.8%, P < 0.001). A new scoring system (R-CHA2DS2-VASc score) derived by assigning an additional point representing renal dysfunction to the CHA2DS2-VASc score could improve its predictive accuracy. The area under the receiver operating characteristic curve increased from 0.68 to 0.71 (P < 0.001). Furthermore, the rate of left ventricular diastolic dysfunction also increased with increasing renal dysfunction. CONCLUSION: Renal dysfunction, associated with left ventricular diastolic dysfunction, was a significant risk factor for POAF after cardiac surgery and may improve the diagnostic accuracy of the CHA2DS2-VASc score.

Lycopene inhibits cyclic strain-induced endothelin-1 expression through the suppression of reactive oxygen species generation and induction of heme oxygenase-1 in human umbilical vein endothelial cells.

Lycopene is the most potent active antioxidant among the major carotenoids, and its use has been associated with a reduced risk for cardiovascular disease (CVD). Endothelin-1 (ET-1) is a powerful vasopressor synthesized by endothelial cells and plays a crucial role in the pathophysiology of CVD. However, the direct effects of lycopene on vascular endothelial cells have not been fully described. This study investigated the effects of lycopene on cyclic strain-induced ET-1 gene expression in human umbilical vein endothelial cells (HUVECs) and identified the signal transduction pathways that are involved in this process. Cultured HUVECs were exposed to cyclic strain (20% in length, 1 Hz) in the presence or absence of lycopene. Lycopene inhibited strain-induced ET-1 expression through the suppression of reactive oxygen species (ROS) generation through attenuation of p22(phox) mRNA expression and NAD(P)H oxidase activity. Furthermore, lycopene inhibited strain-induced ET-1 secretion by reducing ROS-mediated extrace-llular signal-regulated kinase (ERK) phosphorylation. Conversely, lycopene treatment enhanced heme oxygenase-1 (HO-1) gene expression through the activation of phosphoinositide 3-kinase (PI3K)/Akt pathway, followed by induction of the nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation; in addition, HO-1 silencing partially inhibited the repressive effects of lycopene on strain-induced ET-1 expression. In summary, our study showed, for the first time, that lycopene inhibits cyclic strain-induced ET-1 gene expression through the suppression of ROS generation and induction of HO-1 in HUVECs. Therefore, this study provides new valuable insight into the molecular pathways that may contribute to the proposed beneficial effects of lycopene on the cardiovascular system.

Short-term and long-term outcomes of on-pump beating-heart coronary artery bypass surgery in dialysis and non-dialysis patients: a retrospective study in a single center.

BACKGROUND: This study aimed to evaluate the short-term and long-term outcomes of dialysis and non-dialysis patients after On-pump beating-heart coronary artery bypass grafting (OPBH-CABG). METHODS: We retrospectively reviewed medical records of 659 patients underwent OPBH-CABG at our hospital from 2009 to 2019, including 549 non-dialysis patients and 110 dialysis patients. Outcomes were in-hospital mortality, length of stay, surgical complications, post-CABG reintervention, and late mortality. The median follow-up was 3.88 years in non-dialysis patients and 2.24 years in dialysis patients. Propensity matching analysis was performed. RESULTS: After 1:1 matching, dialysis patients had significantly longer length of stay (14 (11-18) vs. 12 (10-15), p = 0.016), higher rates of myocardial infarction (16.85% vs. 6.74%, p = 0.037) and late mortality (25.93% vs. 9.4%, p = 0.005) after CABG compared to non-dialysis patients. No significant differences were observed in in-hospital mortality, complications, or post-CABG reintervention rate between dialysis and non-dialysis groups. CONCLUSIONS: OPBH-CABG could achieve comparable surgical mortality, surgical complication rates, and long-term revascularization in dialysis patients as those in non-dialysis patients. The results show that OPBH-CABG is a safe and effective surgical option for dialysis patients.

Association between renal function, diastolic dysfunction, and postoperative atrial fibrillation following cardiac surgery.

BACKGROUND: Renal dysfunction is associated with a higher rate of atrial fibrillation in clinical practice. This study investigated the associations between renal function, left ventricular (LV) diastolic dysfunction, and postoperative atrial fibrillation (POAF). METHODS AND RESULTS: A total of 265 consecutive patients who underwent cardiac surgery were prospectively enrolled in the study. Echocardiography was performed before cardiac surgery. The patients were divided into 3 groups based on estimated glomerular filtration rate (eGFR) (group 1, ≥90ml·min(-1)·1.73m(-2); group 2, 60-90ml·min(-1)·1.73m(-2); and group 3, <60ml·min(-1)·1.73m(-2)). POAF occurred in 83 of 265 patients (31.3%). The rate of new-onset POAF increased from 15.2% (12/79) in group 1 to 27.8% (27/97) in group 2 and 49.4% (44/89) in group 3 (P<0.001). Further, with increasing renal dysfunction from groups 1 to 3, the rate of LV diastolic dysfunction - defined as E/e' >15 - also increased (group 1, 19.0%; group 2, 38.1%; and group 3, 48.3%; P<0.001). Absolute eGFR was significantly correlated with E/e' ratio (r=-0.39, P<0.001). Renal function remained as the independent predictor of POAF on multivariate analysis (odds ratio, 1.90; 95% confidence interval: 1.26-2.87; P=0.002). CONCLUSIONS: In patients undergoing cardiac surgery, decreased eGFR was associated with an increased rate of LV diastolic dysfunction with a subsequent increase in the rate of POAF.

Association Between Renal Function, Diastolic Dysfunction, and Postoperative Atrial Fibrillation Following Cardiac Surgery.

Background: Renal dysfunction is associated with a higher rate of atrial fibrillation in clinical practice. This study investigated the associations between renal function, left ventricular (LV) diastolic dysfunction, and postoperative atrial fibrillation (POAF). Methods and Results: A total of 265 consecutive patients who underwent cardiac surgery were prospectively enrolled in the study. Echocardiography was performed before cardiac surgery. The patients were divided into 3 groups based on estimated glomerular filtration rate (eGFR) (group 1, ≥90ml·min-1·1.73m-2; group 2, 60-90ml·min-1·1.73m-2; and group 3, <60ml·min-1·1.73m-2). POAF occurred in 83 of 265 patients (31.3%). The rate of new-onset POAF increased from 15.2% (12/79) in group 1 to 27.8% (27/97) in group 2 and 49.4% (44/89) in group 3 (P<0.001). Further, with increasing renal dysfunction from groups 1 to 3, the rate of LV diastolic dysfunction - defined as E/e' >15 - also increased (group 1, 19.0%; group 2, 38.1%; and group 3, 48.3%; P<0.001). Absolute eGFR was significantly correlated with E/e' ratio (r=-0.39, P<0.001). Renal function remained as the independent predictor of POAF on multivariate analysis (odds ratio, 1.90; 95% confidence interval: 1.26-2.87; P=0.002). Conclusions: In patients undergoing cardiac surgery, decreased eGFR was associated with an increased rate of LV diastolic dysfunction with a subsequent increase in the rate of POAF.

Treatment of intragraft stenosis in hemodialysis grafts with Supera stents: A retrospective study.

PURPOSE: To report the patency rates after implantation of an interwoven nitinol stent to salvage failing arteriovenous grafts (AVGs) caused by intragraft stenoses. METHODS: Between May 2018 and May 2020, 21 Supera stents were placed in 20 patients (18 women; mean age: 79.9 years) who had a failing AVG due to repeat intragraft stenoses. Recurrent AVG dysfunction with same intragraft stenosis within 3 months after first time angioplasty was a criterion for stenting. Those with concurrent treatment for other lesions were excluded. RESULTS: The technical success rate was 100%. Intragraft stenoses were treated at a median of 19.7 (interquartile range: 6-36) months after graft creation. Access circuit primary patency rates after stent placement were 84% and 35% at 6 and 12 months, respectively. Access circuit secondary patency rates were 100% at 6 and 12 months and 89% at 18 months. Only one patient presented with graft failure due to proximal drainage vein occlusion. The target lesion patency rates were 100% at 6 months and 75% at 12 months. The rate of reintervention for intragraft lesion was 0.15 procedures per year. Stent distortion did not occur under regular cannulation. CONCLUSION: The interwoven nitinol stent is a promising treatment for failing AVGs with recurrent intragraft stenoses. The 1-year access circuit primary, secondary, and target lesion patency rates were acceptable, with a low reintervention rate. Stent fracture does not occur in areas of needle puncture.

Nicorandil inhibits angiotensin-II-induced proliferation of cultured rat cardiac fibroblasts.

BACKGROUND/AIMS: Nicorandil, an ATP-sensitive potassium (K(ATP)) channel opener, nitric oxide (NO) donor and antioxidant, was shown to exert a variety of pharmacological effects including cardioprotective properties. However, its mechanisms of action are not completely understood. The aims of this study were to examine whether nicorandil may alter angiotensin-II (Ang II)-induced cell proliferation and to identify the putative underlying signaling pathways in rat cardiac fibroblasts. METHODS: Cultured rat cardiac fibroblasts were pretreated with nicorandil, then stimulated with Ang II, and cell proliferation and endothelin-1 (ET-1) expression were examined. The effects of nicorandil on Ang-II-induced reactive oxygen species (ROS) formation and extracellular signal-regulated kinase (ERK) phosphorylation were also examined. In addition, the effects of nicorandil on NO production and endothelial nitric oxide synthase (eNOS) phosphorylation were tested to elucidate the intracellular mechanism. RESULTS: Nicorandil (0.1-10 µmol/l) caused a concentration-dependent inhibition of Ang-II-increased cell proliferation and ET-1 expression which were prevented by the K(ATP) channel blocker glibenclamide (1 µmol/l). Nicorandil also inhibited Ang-II-increased ROS and ERK phosphorylation. In addition, nicorandil was found to increase the NO and eNOS phosphorylation. N-nitro-L-arginine methyl ester, an inhibitor of NOS, and the short interfering RNA transfection for eNOS markedly attenuated the inhibitory effect of nicorandil on Ang-II-induced cell proliferation. CONCLUSION: Our results suggest that nicorandil prevents cardiac fibroblast proliferation, and the inhibitory effect might be associated with the opening K(ATP) channels, by interfering with the generation of ROS, and the activation of the eNOS-NO pathway.

Corrigendum to "Cafestol Inhibits Cyclic-Strain-Induced Interleukin-8, Intercellular Adhesion Molecule-1, and Monocyte Chemoattractant Protein-1 Production in Vascular Endothelial Cells".

[This corrects the article DOI: 10.1155/2018/7861518.].

Uric acid stimulates endothelin-1 gene expression associated with NADPH oxidase in human aortic smooth muscle cells.

AIM: Recent experimental and human studies have shown that hyperuricemia is associated with hypertension and cardiovascular diseases. Elevated levels of endothelin-1 (ET-1) has been regarded as one of the most powerful independent predictors of cardiovascular diseases. For investigating whether uric acidinduced vascular diseases are related to ET-1, the uric acid-induced ET-1 expression in human aortic smooth muscle cells (HASMC) was examined. METHODS: Cultured HASMC treated with uric acid, cell proliferation and ET-1 expression were examined. Antioxidant pretreatments on uric acid-induced extracellular signal-regulated kinases (ERK) phosphorylation were carried out to elucidate the redox-sensitive pathway in proliferation and ET-1 gene expression. RESULTS: Uric acid was found to increase HASMC proliferation, ET-1 expression and reactive oxygen species production. The ability of both N-acetylcysteine and apocynin (1-[4-hydroxy-3-methoxyphenyl]ethanone, a NADPH oxidase inhibitor) to inhibit uric acid-induced ET-1 secretion and cell proliferation suggested the involvement of intracellular redox pathways. Furthermore, apocynin, and p47phox small interfering RNA knockdown inhibited ET-1 secretion and cell proliferation induced by uric acid. Inhibition of ERK by U0126 (1,4-diamino-2,3-dicyano- 1,4-bis[2-aminophenylthio]butadiene) significantly suppressed uric acid-induced ET-1 expression, implicating this pathway in the response to uric acid. In addition, uric acid increased the transcription factor activator protein-1 (AP-1) mediated reporter activity, as well as the ERK phosphorylation. Mutational analysis of the ET-1 gene promoter showed that the AP-1 binding site was an important cis-element in uric acid-induced ET-1 gene expression. CONCLUSION: This is the first observation of ET-1 regulation by uric acid in HASMC, which implicates the important role of uric acid in the vascular changes associated with hypertension and vascular diseases.

Cafestol Inhibits Cyclic-Strain-Induced Interleukin-8, Intercellular Adhesion Molecule-1, and Monocyte Chemoattractant Protein-1 Production in Vascular Endothelial Cells.

Moderate coffee consumption is inversely associated with cardiovascular disease mortality; however, mechanisms underlying this causal effect remain unclear. Cafestol, a diterpene found in coffee, has various properties, including an anti-inflammatory property. This study investigated the effect of cafestol on cyclic-strain-induced inflammatory molecule secretion in vascular endothelial cells. Cells were cultured under static or cyclic strain conditions, and the secretion of inflammatory molecules was determined using enzyme-linked immunosorbent assay. The effects of cafestol on mitogen-activated protein kinases (MAPK), heme oxygenase-1 (HO-1), and sirtuin 1 (Sirt1) signaling pathways were examined using Western blotting and specific inhibitors. Cafestol attenuated cyclic-strain-stimulated intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein- (MCP-) 1, and interleukin- (IL-) 8 secretion. Cafestol inhibited the cyclic-strain-induced phosphorylation of extracellular signal-regulated kinase and p38 MAPK. By contrast, cafestol upregulated cyclic-strain-induced HO-1 and Sirt1 expression. The addition of zinc protoporphyrin IX, sirtinol, or Sirt1 silencing (transfected with Sirt1 siRNA) significantly attenuated cafestol-mediated modulatory effects on cyclic-strain-stimulated ICAM-1, MCP-1, and IL-8 secretion. This is the first study to report that cafestol inhibited cyclic-strain-induced inflammatory molecule secretion, possibly through the activation of HO-1 and Sirt1 in endothelial cells. The results provide valuable insights into molecular pathways that may contribute to the effects of cafestol.

Leptin stimulates endothelin-1 expression via extracellular signal-regulated kinase by epidermal growth factor receptor transactivation in rat aortic smooth muscle cells.

Obesity is a major risk factor for the development of hypertension. Recent studies have suggested that leptin, a 167-amino acid peptide hormone produced by white adipose tissue, is related to the pathogenesis of obesity-related hypertension. However, the signaling mechanisms underlying the effects of leptin remain to be extensively examined. In this study, we found that leptin induced extracellular signal-regulated kinase phosphorylation and endothelin-1 expression in rat aortic smooth muscle cells. Both PD98059 and U0126, inhibitors of the upstream activator of mitogen-activated protein kinase kinase, inhibited augmentation of endothelin-1 expression stimulated with leptin. Leptin induced significant tyrosine phosphorylation of epidermal growth factor receptor, which was significantly attenuated by two inhibitors, an epidermal growth factor receptor tyrosine kinase inhibitor, AG1478, and a broad-spectrum matrix metalloproteinase inhibitor, GM6001. This indicates that the pathway of epidermal growth factor receptor transactivation induced by leptin is dependent on proteolytically released epidermal growth factor receptor ligands. Pretreatment of cells with AG1478 significantly reduced the degree of phosphorylation of extracellular signal-regulated kinase and endothelin-1 expression. Our results reveal that epidermal growth factor receptor transactivation is involved in the leptin signaling pathway in vascular smooth muscle cells, which may be related to the increased risk of hypertension and other cardiovascular diseases in obese subjects.

Resveratrol inhibits angiotensin II-induced endothelin-1 gene expression and subsequent proliferation in rat aortic smooth muscle cells.

Resveratrol is a phytoestrogen naturally found in grapes and is the major constituent of wine thought to have a cardioprotective effect. The aims of this study were to examine whether resveratrol alters angiotenisn II-induced cell proliferation and endothelin-1 gene expression and to identify the putative underlying signaling pathways in rat aortic smooth muscle cells. Cultured rat aortic smooth muscle cells were preincubated with resveratrol then stimulated with angiotensin II, after which [3H]thymidine incorporation and endothelin-1 gene expression were examined. The intracellular mechanism of resveratrol in cellular proliferation and endothelin-1 gene expression was elucidated by examining the phosphorylation level of angiotensin II-induced extracellular signal-regulated kinase (ERK). The inhibitory effects of resveratrol (1-100 microM) on angiotensin II-induced DNA synthesis and endothelin-1 gene expression were demonstrated with Northern blot and promoter activity assays. Measurements of 2'7'-dichlorofluorescin diacetate, a redox-senstive fluorescent dye, showed a resveratrol-mediated inhibition of intracellular reactive oxygen species generated by the effects of angiotensin II. The inductive properties of angiotensin II and H2O2 on ERK phosphorylation and activator protein-1-mediated reporter activity were found reversed with resveratrol and antioxidants such as N-acetyl-cysteine. In summary, we speculate that resveratrol inhibits angiotensin II-induced cell proliferation and endothelin-1 gene expression, and does so in a manner which involves the disruption of the ERK pathway via attenuation of reactive oxygen species generation. Thus, this study provides important insight into the molecular pathways that may contribute to the proposed beneficial effects of resveratrol on the cardiovascular system.

Lycopene Inhibits Urotensin-II-Induced Cardiomyocyte Hypertrophy in Neonatal Rat Cardiomyocytes.

This study investigated how lycopene affected urotensin-II- (U-II-) induced cardiomyocyte hypertrophy and the possible implicated mechanisms. Neonatal rat cardiomyocytes were exposed to U-II (1 nM) either exclusively or following 6 h of lycopene pretreatment (1-10 µ M). The lycopene (3-10 µ M) pretreatment significantly inhibited the U-II-induced cardiomyocyte hypertrophy, decreased the production of U-II-induced reactive oxygen species (ROS), and reduced the level of NAD(P)H oxidase-4 expression. Lycopene further inhibited the U-II-induced phosphorylation of the redox-sensitive extracellular signal-regulated kinases. Moreover, lycopene treatment prevented the increase in the phosphorylation of serine-threonine kinase Akt and glycogen synthase kinase-3beta (GSK-3 ß ) caused by U-II without affecting the protein levels of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN). However, lycopene increased the PTEN activity level, suggesting that lycopene prevents ROS-induced PTEN inactivation. These findings imply that lycopene yields antihypertrophic effects that can prevent the activation of the Akt/GSK-3 ß hypertrophic pathway by modulating PTEN inactivation through U-II treatment. Thus, the data indicate that lycopene prevented U-II-induced cardiomyocyte hypertrophy through a mechanism involving the inhibition of redox signaling. These findings provide novel data regarding the molecular mechanisms by which lycopene regulates cardiomyocyte hypertrophy.

Urotensin II induces interleukin 8 expression in human umbilical vein endothelial cells.

BACKGROUND: Urotensin II (U-II), an 11-amino acid peptide, exerts a wide range of actions in cardiovascular systems. Interleukin-8 (IL-8) is secreted by endothelial cells, thereby enhancing endothelial cell survival, proliferation, and angiogenesis. However, the interrelationship between U-II and IL-8 as well as the detailed intracellular mechanism of U-II in vascular endothelial cells remain unclear. The aim of this study was to investigate the effect of U-II on IL-8 expression and to explore its intracellular mechanism in human umbilical vein endothelial cells. METHODS/PRINCIPAL FINDINGS: Primary human umbilical vein endothelial cells were used. Expression of IL-8 was determined by real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and luciferase reporter assay. Western blot analyses and experiments with specific inhibitors were performed to reveal the downstream signaling pathways as concerned. U-II increased the mRNA/protein levels of IL-8 in human umbilical vein endothelial cells. The U-II effects were significantly inhibited by its receptor antagonist [Orn(5)]-URP. Western blot analyses and experiments with specific inhibitors indicated the involvement of phosphorylation of p38 mitogen-activated protein kinase and extracellular signal-regulated kinase in U-II-induced IL-8 expression. Luciferase reporter assay further revealed that U-II induces the transcriptional activity of IL-8. The site-directed mutagenesis indicated that the mutation of AP-1 and NF-kB binding sites reduced U-II-increased IL-8 promoter activities. Proliferation of human umbilical vein endothelial cells induced by U-II could be inhibited significantly by IL-8 RNA interference. CONCLUSION/SIGNIFICANCE: The results show that U-II induces IL-8 expression in human umbilical vein endothelial cells via p38 mitogen-activated protein kinase and extracellular signal-regulated kinase signaling pathways and IL-8 is involved in the U-II-induced proliferation of human umbilical vein endothelial cells.

Clinical utility of CHADS2 and CHA2DS2-VASc scoring systems for predicting postoperative atrial fibrillation after cardiac surgery.

OBJECTIVES: The presence of postoperative atrial fibrillation predicts a higher short- and long-term mortality rates; however, no scoring system has been used to discriminate patients at high risk for this complication. The aim of this study was to investigate whether the CHADS2 and CHA2DS2-VASc scores are useful risk assessment tools for new-onset atrial fibrillation after cardiac surgery. METHODS: A total of 277 consecutive patients who underwent cardiac surgery were prospectively included in this risk stratification study. We calculated the CHADS2 and CHA2DS2-VASc scores from the data collected. The primary end point was the development of postoperative atrial fibrillation within 30 days after cardiac surgery. RESULTS: Eighty-four (30%) of the patients had postoperative atrial fibrillation at a median of 2 days (range, 0-27 days) after cardiac surgery. The CHADS2 and CHA2DS2-VASc scores were significant predictors of postoperative atrial fibrillation in separate multivariate regression analyses. The Kaplan-Meier analysis obtained a higher postoperative atrial fibrillation rate when based on the CHADS2 and CHA2DS2-VASc scores of at least 2 than when based on scores less than 2 (both log rank, P < .001). In addition, the CHA2DS2-VASc scores could be used to further stratify the patients with CHADS2 scores of 0 or 1 into 2 groups with different postoperative atrial fibrillation rates at a cutoff value of 2 (12% vs 32%; P = .01). CONCLUSIONS: CHADS2 and CHA2DS2-VASc scores were predictive of postoperative atrial fibrillation after cardiac surgery and may be helpful for identifying high-risk patients.

Nicorandil attenuates cyclic strain-induced endothelin-1 expression via the induction of activating transcription factor 3 in human umbilical vein endothelial cells.

Nicorandil is an adenosine triphosphate-sensitive potassium channel opener that combines an organic nitrate and a nicotinamide group which respectively confer to nicorandil the additional properties of being a nitric oxide (NO) donor and antioxidant; it also induces vasodilation, decreases the blood pressure, and protects the heart. However, the intracellular mechanism of nicorandil remains to be delineated. The aims of this study were to test the hypothesis that nicorandil alters strain-induced endothelin-1 secretion and NO production, and to identify the putative underlying signaling pathways in human umbilical vein endothelial cells (HUVECs). Cultured HUVECs were exposed to cyclic strain in the presence of nicorandil; endothelin-1 expression was examined by reverse-transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay. Activation of extracellular signal-regulated protein kinase (ERK), endothelial NO synthase (eNOS), and activating transcription factor (ATF)-3 was assessed by Western blot analysis. We show that nicorandil inhibited strain-induced endothelin-1 expression. Nicorandil also inhibited strain-increased reactive oxygen species formation and ERK phosphorylation. On the contrary, NO production, eNOS phosphorylation, and ATF3 expression were enhanced by nicorandil; however, L-NAME (an inhibitor of eNOS) and LY294002 (an inhibitor of phosphatidylinositol 3-kinase) inhibited nicorandil-increased ATF3 expression. Moreover, treatment of HUVECs with either an NO donor (NOC18; 3,3-bis[aminoethyl]-1-hydroxy-2-oxo-1-triazene) or an ATF3 activator (MG-132; carbobenzoxy-L-leucyl-L-leucyl-L-leucinal) resulted in repression of strain-induced endothelin-1 expression. Furthermore, L-NAME, and small interfering RNA transfection of eNOS also partially attenuated the inhibitory effect of nicorandil on strain-induced endothelin-1 expression. We demonstrate for the first time that nicorandil inhibits strain-induced endothelin-1 secretion via an increase in NO and upregulation of ATF3 in HUVECs. This study provides important new insights into the molecular pathways that may contribute to the beneficial effects of nicorandil in the cardiovascular system.

Spontaneous rupture of left ventricular true aneurysm.

The rupture of left ventricular true aneurysm is a rare event. We report the case of a 52-year-old man who presented to the emergency department with cardiac tamponade that was due to a ruptured left ventricular true aneurysm. An emergency operation was successfully performed to address this rare event.

Role of mitogen-activated protein kinase pathway in reactive oxygen species-mediated endothelin-1-induced beta-myosin heavy chain gene expression and cardiomyocyte hypertrophy.

Endothelin-1 (ET-1) has been found to increase cardiac beta-myosin heavy chain (beta-MyHC) gene expression and induce hypertrophy in cardiomyocytes. ET-1 has been demonstrated to increase intracellular reactive oxygen species (ROS) in cardiomyocytes. The exact molecular mechanism by which ROS regulate ET-1-induced beta-MyHC gene expression and hypertrophy in cardiomyocytes, however, has not yet been fully described. We aim to elucidate the molecular regulatory mechanism of ROS on ET-1-induced beta-MyHC gene expression and hypertrophic signaling in neonatal rat cardiomyocytes. Following stimulation with ET-1, cultured neonatal rat cardiomyocytes were examined for 3H-leucine incorporation and beta-MyHC promoter activities. The effects of antioxidant pretreatment on ET-1-induced cardiac hypertrophy and mitogen-activated protein kinase (MAPKs) phosphorylation were studied to elucidate the redox-sensitive pathway in cardiomyocyte hypertrophy and beta-MyHC gene expression. ET-1 increased 3H-leucine incorporation and beta-MyHC promoter activities, which were blocked by the specific ET(A) receptor antagonist BQ-485. Antioxidants significantly reduced ET-1-induced 3H-leucine incorporation, beta-MyHC gene promoter activities and MAPK (extracellular signal-regulated kinase, p38, and c-Jun NH2 -terminal kinase) phosphorylation. Both PD98059 and SB203580 inhibited ET-1-increased 3H-leucine incorporation and beta-MyHC promoter activities. Co-transfection of the dominant negative mutant of Ras, Raf, and MEK1 decreased the ET-1-induced beta-MyHC promoter activities, suggesting that the Ras-Raf-MAPK pathway is required for ET-1 action. Truncation analysis of the beta-MyHC gene promoter showed that the activator protein-2 (AP-2)/specificity protein-1 (SP-1) binding site(s) were(was) important cis-element(s) in ET-1-induced beta-MyHC gene expression. Moreover, ET-1-induced AP-2 and SP-1 binding activities were also inhibited by antioxidant. These data demonstrate the involvement of ROS in ET-1-induced hypertrophic responses and beta-MyHC expression. ROS mediate ET-1-induced activation of MAPK pathways, which culminates in hypertrophic responses and beta-MyHC expression.