Normal mode energy estimation based on reconstructing the incoherent beamformed outputs from a horizontal array.

The acoustic pressure field in many underwater environments is well described by a superposition of normal modes. The normal modes can be used for source localization and environmental inversion. However, the wavenumber resolution of traditional normal mode filtering methods for a small-aperture horizontal array is usually not sufficient to identify individual modes in a shallow water waveguide. This paper proposes an original method of normal mode energy estimation to remove the energy leakage between modes. The modal energy is defined as the square of the modal amplitude. This method is to reconstruct the incoherent beamformed outputs in wavenumber domain for a horizontally moving source. The adaptive beamforming is used to suppress interference and improve output signal-to-noise ratio. The uncertainty of modal phase velocity has also been considered in this method. The proposed method can provide more accurate estimates of modal energy for a small-aperture horizontal array than the traditional mode filtering methods, such as the matched filter, the least squares mode filter, the regularized-least squares mode filter, and the maximum a posteriori mode filter, in simulations and experiments.

Long-term Impact of Thrombus Aspiration in Patients With ST-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention.

Thrombus aspiration (TA) during primary percutaneous coronary intervention (PPCI) is reported to improve myocardial reperfusion. However, the long-term prognostic implication of TA remains unclear. We aimed to investigate the influence of adjunctive TA on long-term outcomes in ST-segment elevation myocardial infarction (STEMI) patients undergoing PPCI. All STEMI patients from China that included in the TOTAL trial who were ≥18 years old and referred for PPCI within the 12 hours after symptom onset between January 2011 and November 2012 were retrospectively analyzed. Patients were divided into 2 groups based on the use of TA or not. The primary efficacy outcomes were 5-year major adverse cardiac events, a composite of cardiovascular death, recurrent MI, cardiogenic shock, or heart failure hospitalization. The primary safety outcome was a 5-year stroke. A total of 563 patients were included. The incidence rate of major adverse cardiac events at 5 years in the TA group was similar to that in the PCI group (hazard ratio [HR] 0.70; 95% confidence interval [CI] 0.42 to 1.17). In addition, TA was significantly associated with a nearly sevenfold increased risk of stroke at 5 years compared with PCI alone (HR 7.32, 95% CI 1.33 to 40.31). Our propensity scoring match analyses suggested that patients with an occluded lesion might benefit from the TA (HR 0.24, 95% CI 0.08 to 0.70). In conclusion, TA is not associated with improved outcomes in patients with STEMI but may have an adverse impact on stroke. Patients with an occluded infarct-related artery could benefit from the TA.

Measurement and modeling of sound propagation over continental slope in the South China Sea.

Measurements along two ship tracks were obtained in an experiment to investigate the properties of acoustic propagation over the continental slope in the South China Sea. The measured data show a notable difference in transmission loss about 35 dB as sound crosses different geodesic paths. Numerical simulations indicate that the range and azimuth-dependent geological properties control the level of the transmission loss and lead to this large transmission loss fluctuation. In addition, the model also suggests some small-scale features of horizontal refraction effect caused by irregular topography, but they are not observed in the measured data.

Seasonally-invariant head wave speed extracted from ocean noise cross-correlation.

Ambient noise was recorded continuously for 9 months by two horizontal arrays deployed in shallow water with a horizontal separation of approximately 0.5 km. Stable empirical Green's functions (EGFs) were extracted from ambient noise correlations between the two arrays. The EGFs have three distinct envelopes which correspond to the head waves, direct waves, and surface-reflected waves. The arrival time of the head wave was almost constant with season. Corresponding simulations were carried out, and implied that the relatively small penetration depth of heat flow is the main reason for the seasonally-invariant head wave speed.

Acute glycemic variability on admission predicts the prognosis in hospitalized patients with coronary artery disease: a meta-analysis.

PURPOSE: Increased glycemic variability has been related with poor prognosis in patients with coronary artery disease (CAD). However, whether diabetic status or subtype of CAD could affect the association remains unknown. We performed a meta-analysis to systematically evaluate the association between the mean amplitude of glycemic excursions (MAGE) on continuous glucose monitoring and the incidence of major adverse cardiovascular events (MACEs) in CAD patients. METHODS: Relevant prospective cohort studies were identified through search of PubMed, Embase, WanFang, and CNKI databases. A random-effect model was used to pool the results. Subgroup analyses were performed to evaluate the influences of the predefined study characteristics on the outcome. RESULTS: Eleven cohort studies with 2666 hospitalized patients with acute coronary syndrome (ACS) or stable CAD for percutaneous coronary intervention were included. Pooled results showed that higher MAGE at admission was associated with higher incidence of MACEs during follow-up (adjusted relative risk [RR]: 1.84, p < 0.001; I2 = 12%). Stratified analyses showed that the association between higher MAGE and higher risk of MACEs in CAD patients were consistent in patients with or without diabetes, and in those with ACS or stable CAD (p for subgroup difference both >0.05). Significant publication bias was detected (p = 0.041). Trim-and-fill analysis retrieved three studies to generate symmetrical funnel plots. Meta-analysis that incorporated these studies showed similar results (RR: 1.80, p < 0.001). CONCLUSIONS: Increased glycemic variability may be associated with poor prognosis in CAD patients regardless of the diabetic status and the subtype of CAD.

Passive ocean acoustic tomography in shallow water.

It has been demonstrated that an estimate of an empirical Green's function (EGF) can be extracted from the ocean ambient noise cross-correlation functions, which can provide an alternative method for ocean acoustic tomography. However, the requirement for a long recording time to obtain EGFs with a high signal-to-noise ratio limits the application. This article focuses on using array signal processing to accelerate the convergence rate of EGFs between two horizontally separated arrays. With the extracted EGFs and data assimilation, ocean sound speed profiles (SSPs) can be inverted every 2 h in shallow water. The experimental results indicate that the variation in ocean SSPs can be reconstructed with reasonable agreement using an average variance of 1.14 m/s over three months.

Impact of Physician-Coordinated Intensive Follow-Up on Long-Term Medical Costs in Patients with Unstable Angina Undergoing Percutaneous Coronary Intervention.

BACKGROUND: To investigate the impact of professional physician-coordinated intensive follow-up on long-term expenditures after percutaneous coronary intervention (PCI) in unstable angina (UA) patients. METHODS: In this study, there were 669 UA patients who underwent successful PCI and followed up for 3 years, then divided into the intensive follow-up group (N = 337), and the usual follow-up group (N = 332). Patients were provided with detailed discharge information and individualized follow-up schedules. The intensive group received the extra follow-up times and medical consultations, and all patients were followed up for approximately 3 years. RESULTS: At the 3-year mark after PCI, the cumulative major adverse cardiac events (MACE), recurrence of myocardial ischemia, cardiac death, all-cause death and revascularization in the intensive group were lower than in the usual group. Additionally, the proportion of good medication adherence was significantly higher than in the usual group (56.4% vs. 46.1%, p < 0.001). The hospitalization daytime, total hospitalization cost and total medical cost in the intensive group were lower. Multiple linear regression showed that diabetes, hypertension, intensive follow-up and good medication adherence were associated with emergency and regular clinical cost (p < 0.05), the re-hospitalization cost (p < 0.05) and the total medical cost (p < 0.05) of patient care. Intensive follow-up and good adherence were negatively correlated with the cost of re-hospitalization (standardized coefficients = -0.132, -0.128, p < 0.05) and total medical costs (standardized coefficients = -0.072, -0.086, p < 0.05). CONCLUSIONS: Intensive follow-up can reduce MACE, improve medication adherence and save long-term total medical costs, just by increasing the emergency and regular clinical visits cost in UA patients after PCI.

Impacts of intensive follow-up on the long-term prognosis of percutaneous coronary intervention in acute coronary syndrome patients - a single center prospective randomized controlled study in a Chinese population.

OBJECTIVES: To investigate the impact of cardiologist-coordinated intensive follow-up on the long-term prognosis of percutaneous coronary intervention in Chinese patients. METHODS: We recruited 964 patients who had acute coronary syndrome and underwent successful percutaneous coronary intervention in the First Hospital Affiliated to Henan University of Science and Technology, China. Participants were randomly assigned into the intensive follow-up (n = 479) and usual follow-up group (control group, n = 485). They received secondary prevention education during hospitalization and telephone follow-ups after discharge. The control group received telephone calls from nurses, while the intensive follow-up group received telephone calls and medical consultations from cardiologists. Both groups were followed up for 36 months. RESULTS: (1) At 36 months, the proportions of all-cause death, cardiac death and cumulative major adverse cardiovascular events (MACEs) were 5.3%, 4.4% and 18.6% in the intensive follow-up group. These events were significantly lower than in the control group (10.1%, 9.3 % and 28.8% (p = 0.004, p = 0.003 and p < 0.001). (2) Multivariable Cox regression analysis identified intensive follow-up as an independent predictor of survival, cardiac death-free survival and MACE-free survival. (hazard ratio (HR) = 0.487, 95% confidence interval (CI) 0.298-0.797, p = 0.004; HR = 0.466, 95% CI 0.274-0.793, p = 0.005; HR = 0.614, 95% CI 0.464-0.811, p = 0.001). Kaplan-Meier analysis revealed that patients in the intensive follow-up groups had longer survival (log rank = 8.565, p = 0.003), cardiac death-free survival (log rank = 8.769, p = 0.003) and MACE-free survival (log rank = 15.928, p < 0.001). (3) The average medical cost was significantly less in the intensive follow-up group, especially the cost for re-hospitalization (US$582.74 ± 1753.20 vs. US$999.32 ± 2434.57, p = 0.003). The bleeding events were similar. (4) Patients in the intensive follow-up group had significantly better controls of cardiovascular risk factors and medication adherence. CONCLUSIONS: A cardiologist-coordinated intensive follow-up program markedly decreased cardiovascular risk factors, reduced medical costs, promoted medication adherence and improved the long-term prognosis of patients after percutaneous coronary intervention in the Chinese population.

Elevated risk of an intermediate or high SYNTAX score in subjects with impaired fasting glucose.

OBJECTIVE: This study was designed to determine the SYNTAX score under different fasting plasma glucose (FPG) states in Chinese patients undergoing coronary angiography, particularly subjects with impaired FPG. METHODS: Four hundred and forty-six subjects undergoing coronary angiography were enrolled in this study and divided into four groups based on the FPG level or a history of type 2 diabetes mellitus (T2DM): normal FPG, impaired FPG, known and previously unknown T2DM. RESULTS: The angiographic SYNTAX scores were higher in the subjects with known (p<0.001) or previously unknown (p<0.001) T2DM than in those with normal FPG. There were significant differences in the number of diseased coronary artery vessels between the subjects with known (p<0.01) or unknown T2DM (p<0.05) and the subjects with normal FPG. However, there were no significant differences in the SYNTAX score or the number of diseased coronary artery vessels between the subjects with impaired FPG and those with normal FPG. The subjects with impaired FPG (2.917-fold, p=0.004) and known (3.064-fold, p=0.000) or previously unknown (3.301-fold, p=0.000) T2DM exhibited a significantly elevated risk of having an intermediate or high SYNTAX score compared with the subjects with normal FPG. CONCLUSION: Chinese subjects with impaired FPG have a significantly elevated risk of having an intermediate or high SYNTAX score, indicating a risk of severe coronary artery lesions. Subjects with known or previously unknown T2DM may have severe coronary artery lesions. These findings suggest the importance of achieving better glycemic control in order to prevent coronary atherosclerosis and improve the cardiovascular prognosis.

Association between left ventricular end-diastolic pressure and coronary artery disease as well as its extent and severity.

Patients with myocardial ischemia exhibit increased left ventricular end-diastolic pressure (LVEDP). The study was to evaluate the relationship between LVEDP measured by left cardiac catheterization and coronary artery disease (CAD) as well as its extent and severity evaluated by coronary angiography (CAG). 912 patients who underwent CAG and left cardiac catheterization were enrolled. There were 313 patients without CAD and 599 with CAD according to CAG. The extent and severity of coronary artery was evaluated by number of vessels and Gensini score. Analyze the correlation of LVEDP and CAD as well as its extent and severity. LVEDP was significantly higher in CAD patients than non-CAD (9.58±5.78 mmHg vs 10.9±5.46 mmHg, P<0.001), and was correlated independently with the presence of CAD (OR = 0.11, per 5 mmHg increase, 95% CI 1.02-1.29, P = 0.02). LVEDP was increased with an increase of number of vessels. By linear regression analysis, LVEDP was significantly associated with Gensini score (standardized ß = 0.034, P = 0.001). In non-CAD group, LVEDP was only correlated with age (r = 0.123, P = 0.030). In conclusion, our findings suggest that elevated LVEDP was significantly associated with CAD as well as its extent and severity. LVEDP was only correlated with age in non-CAD patients. LVEDP measurement provides incremental clinical value for CAD and non-CAD patients.

Angiotensin II and Aldosterone stimulating NF-kappaB and AP-1 activation in hepatic fibrosis of rat.

BACKGROUND/AIMS: Intrahepatic renin-angiotensin-aldosterone system (RAAS) plays a key role in the fibrogenesis of liver. However, the signal transduction mechanism underlying effects of Angiotensin II (Ang II) and Aldosterone (Aldo) on Nuclear Factor-kappaB (NF-kappaB) and active protein-1 (AP-1) pathway in hepatic fibrogenesis remains to be fully elucidated. The present study aims to investigate the signal transduction mechanism underlying effects of Ang II and Aldo on NF-kappaB and AP-1 pathway during hepatic fibrogenesis. METHODS: To assess the effect of AECI and Angiotensin II type 1 receptor (AT-1 receptor) blocker on NF-kappaB activity in liver, a model of fibrosis was performed in rat. In vitro, hepatic stellate cells (HSCs)-T6 cells were preincubated for 1 h or not with U0126, a specific inhibitor of extracellular signal regulated kinase (ERK), irbesartan, and N-acetylcysteine prior to exposure to Ang II or Aldo for the indicated times. DNA binding activity of NF-kappaB and AP-1 were analyzed by Electrophoretic mobility shift assay (EMSA). Western blot was used to detect expression of IkappaBalpha and Phospho-P42/44. RT-PCR was used to detect the expressions of tumor necrosis factor alpha (TNFalpha) mRNA and alpha1 (I) procollagen mRNA. RESULTS: AECI and AT-1 receptor blocker exert anti-fibrosis effect through inhibiting NF-kappaB activation in liver. Ang II and Aldo increase HSCs NF-kappaB activity and NF-kappaB target gene-TNFalpha expression by inhibiting IkappaBalpha expression in a redox-sensitive manner. Ang II and Aldo also markedly increase HSCs AP-1 activity and AP-1 target gene-alpha1 (I) procollagen mRNA expression via ERK1/2 pathway in a redox-sensitive manner. CONCLUSIONS: These results show that stimulation of NF-kappaB and AP-1 pathway mediate hepatic fibrogenesis induced by intrahepatic RAAS.

[Aldosterone stimulates alpha1-(1) procollagen mRNA expression in HSC via activation of ERK1/2 and AP-1].

OBJECTIVE: It has been known that the intrahepatic renin-angiotensin-aldosterone system (RAAS) plays a key role in the fibrogenesis in livers. Aldosterone (Aldo), the principal effector molecule of the RAAS, exerts local effects on cell growth and fibrogenesis. However, the signal transduction mechanisms underlying the effects of Aldo on hepatic fibrogenesis remain to be fully elucidated. The present study aims to investigate the signal transduction mechanism underlying the effects of Aldo on the signal passageway of active protein-1 (AP-1). METHODS: In vitro, HSCs-T6 cell line was treated with Aldo for 10 min, 30 min, 60 min, 120 min and 180 min, and protein expression of Phospho-P42/44 was detected by Western blot. In addition, HSCs-T6 cell line was preincubated for 60 min or not with U0126 (an inhibitor of the MAPK/ERK kinase), and also with antioxidant-N-acetylcysteine (NAC) prior to exposure to Aldo for the indicated times. Protein expression of Phospho-P42/44 was measured by Western blot. DNA biding activity of AP-1 was analyzed by electrophoretic gel mobility shift assay (EMSA). By means of RT-PCR, expression of alpha1(1) procollagen mRNA was detected. RESULTS: Aldo stimulated HSC via extracellular signal-regulated kinase (ERK1/2) pathway. Time course experiments showed that Aldo induced Phospho-P42/44 expression, which was abrogated by U0126, reaching a maximum at 10 minutes, and then declined progressively. NAC inhibited the Phospho-P42/44 expression. EMSA showed that stimulation of HSC by Aldo markedly increased AP-1 DNA binding activity. U0126 markedly reduced AP-1 DNA binding activity induced by Aldo; NAC partly decreased AP-1 activity induced by Aldo. Aldo up-regulated expression of alpha1(1) procollagen mRNA, which was attenuated by U0126 and NAC. CONCLUSION: Stimulation of HSC by Aldo results in activation of AP-1 via ERK1/2 pathway, leading to up-regulation of AP-1 target gene alpha1(1) procollagen mRNA expression.

[Angiotensin II and aldosterone stimulate alpha1-(I) procollagen mRNA expression in hepatic stellate cells via activation of ERK1/2 and AP-1].

OBJECTIVE: To investigate the signal transduction mechanism underlying the effects of angiotensin II (Ang II) and aldosterone (Aldo) on the signal passageway of active protein-1 (AP-1). METHODS: In vitro, Hepatic stellate cells (HSCs) of the line HSC-T6 were cultured and treated with Ang II or Aldo, the principal effector molecules of the renin-angiotensin-aldosterone system (RAAS) for 10, 30, 60, 120, and 180 minutes respectively. The protein expression of phospho-P42/44 was detected by Western blotting. In addition, HSC-T6 cells were preincubated for 60 min with U0126, an inhibitor of MAPK/ERK kinase, irbesartan, an AT-1 receptor blocker, N-acetylcysteine (NAC), antioxidant, angiotensin converting enzyme inhibitor (ACEI), or tumor necrosis factor alpha (TNFalpha) prior to exposure to Ang II or Aldo. Then the protein expression of phospho-P42/44 was measured by Western blotting. The DNA biding activity of AP-1 was analyzed by electrophoretic gel mobility shift assay (EMSA). By means of RT-PCR, the mRNA expression of alpha1 (I) procollagen was detected. RESULTS: The levels of phopho-ERK1/2 protein increased after the treatment of Ang II and Aldo at all time points and both peaked 10 minutes after (both P < 0.01). The levels of phopho-ERK1/2 protein of the irbesartan + Ang II and U0126 + Ang II groups were significantly lower than that of the Ang II group (both P < 0.01). The level of phopho-ERK1/2 protein of the Ang II group was lower than that of the TNFalpha group, however, was especially significantly lower than that of the Ang II + TNFalpha group (P < 0.01). The level of phopho-ERK1/2 protein of the U0126 + Aldo group was significantly lower than that of the Aldo group (P < 0.01). The phopho-ERK1/2 protein level of the NAC + Aldo group was not significantly different from that of the Aldo group (P > 0.05). The phopho-ERK1/2 protein level of the Aldo group was lower than that of the TNFalpha group, however, was especially significantly lower than that of the Aldo + TNFalpha group (P < 0.01). The AP-1 DNA binding protein increased after the treatment of Ang II and peaked 30 min after. U0126, irbesartan, and NAC, as well as ACEUI, significantly inhibited the increased AP-1 DNA binding activity induced by Ang II. The AP-1 DNA binding protein increased after the treatment of Aldo and peaked twice, 30 min and 240 min after. U0126 and NAC significantly and NAC partly inhibited the increased AP-1 DNA binding activity induced by Aldo. CONCLUSION: Stimulation of HSC by Ang II and Aldo results in activation of AP-1 via ERK1/2 pathway leading to up-regulation of AP-1 target gene alpha1 (I) procollagen mRNA expression.

[Aldosterone stimulating PDGF-B expression in HSC via activation of EGR-1].

OBJECTIVE: It is known that intrahepatic renin-angiotensin-aldosterone system (RAAS) plays a key role in liver fibrogenesis. Aldosterone (Aldo), the principal effector molecule of the RAAS, exerts local effects on cell growth and fibrogenesis. However, the signal transduction mechanisms underlying the effects of Aldo on hepatic fibrogenesis remain to be fully elucidated. The present study aims to investigate the signal transduction mechanism underlying the effects of Aldo on extracellular signal-regulated kinase 1/2 (ERK1/2), early growth response-1 (EGR-1) and on the platelet-derived growth factor-B (PDGF-B). METHODS: In vitro, hepatic stellate cell (HSC)-T6 cell line was treated with Aldo for 10 min, 0.5 h, 1 h, 2 h and 3 h. Protein expression of phospho-p42/44 was detected by Western blot. In addition, HSC-T6 were preincubated for 1 h or not at all with U0126 (an inhibitor of the MAPK/ERK kinase), and antioxidant-N-acetylcysteine (NAC) prior to exposure to Aldo for the indicated times. Protein expressions of phospho-p42/44 and PDGF-B were measured by Western blot. DNA biding activity of EGR-1 was analyzed by electrophoretic gel mobility shift assay (EMSA). By means of immunohistochemistry, expression of PDGF-B was detected. RESULTS: Aldo induced phospho-p42/44 expression could be abrogated by U0126; NAC did not inhibit phospho-p42/44 expression. Gel shift study showed that stimulation of HSC by Aldo markedly increased the EGR-1 DNA binding activity, which was abrogated by U0126, reaching a maximum at 60 minutes, and then declined progressively. NAC did not reduce the EGR-1 activity. Aldo increased the PDGF-B protein level in HSC, which was not attenuated by NAC and U0126. CONCLUSIONS: Stimulation of HSC by Aldo results in activation of EGR-1 via ERK1/2 pathway, leading to up-regulation of PDGF-B expression.

ACEI attenuates the progression of CCl4-induced rat hepatic fibrogenesis by inhibiting TGF-beta1, PDGF-BB, NF-kappaB and MMP-2,9.

AIM: Angiotensin II has pro-fibrotic function in the liver. Blockade of the renin-angiotensin-aldosterone-system (RAAS) attenuates hepatic fibrosis. The aim of the present study was to determine the mechanism of angiotensin-converting enzyme inhibitor (ACEI) on the progression of rat hepatic fibrosis. METHODS: Forty male Wistar rats were divided into three groups. Model group (Mo): The rats were injected subcutaneously with 40% of CCl(4) 0.25 mL/100 g. Perindopril group (Pe): The rats were injected subcutaneously with 40% of CCl(4). Perindopril, equivalent to 2 mg/(kg.d), was administrated. Control group (Nc): the rats were treated with olive oil only. After 4 and 6 wk, the rats were killed. The liver sections were stained with Masson. The protein expressions of AT1R, TGF-beta1 and PDGF-BB were examined by Western blot. Nuclear factor kappaB (NF-kappaB) DNA binding activity was examined by EMSA (Electrophoretic gel mobility shift assay). Matrix metalloproteinase-2,9 (MMP-2,9) activity was assessed by zymography. Serum laminin (LN) and hyaluronic acid (HA) were measured using radioimmunoassays. RESULTS: Using Western blot, we clearly provided direct evidence for the expression of AT1R in liver. The expression was up-regulated when fibrogenesis occurred. Perindopril treatment significantly reduced mean fibrosis score, protein levels of AT1R, TGF-beta1 and PDGF-BB, serum levels of HA and LN, and the activity of MMP-2,9. NF-kappaB DNA binding activity markedly increased in model group, perindopril treatment considerably reduced NF-kappaB DNA binding activity. CONCLUSION: Perindopril attenuates CCl(4)-induced hepatic fibrogenesis of rat by inhibiting TGF-beta1, PDGF-BB, NF-kappaB and MMP-2,9.

[Effects of angiotensin II and aldosterone on NF-kappaB binding activity in hepatic stellate cells].

OBJECTIVE: To investigate the signal transduction mechanism underlying the effects of angiotensin II (AngII) and aldosterone (Aldo) on nuclear factor-kappaB (NF-kappaB) DNA binding activity. METHODS: Sixty male Wistar rats were randomly divided into 4 groups: model group (Mo group), injected with CCl(4) subcutaneously twice a week to establish a model of hepatic fibrosis; perindopril group (Pe group), injected with CCl(4) subcutaneously twice a week and perfused with perindopril once a day; losartan group (Lo group), injected with CCl(4) subcutaneously twice a week and perfused with losartan once a day; and control group (Nc group), injected with olive oil subcutaneously. The rats were killed in batches respectively 4 and 6 weeks after and their livers were collected to undergo Masson staining and be observed by light microscope. Electrophoretic gel mobility shift assay (EMSA) was used to detect the NF-kappaB DNA binding activity in the liver tissues. Western blotting was used to detect the expression of IkappaBalpha in the plasma protein. Hepatic stellate cells (HSCs)-T6 were cultured and preincubated for 1 h or not with U0126 (an inhibitor of MAPK/ERK kinase MEK), irbesartan (an AT-1 receptor blocker), and N-acetylcysteine (NAC, an antioxidant), angiotensin-converting enzyme inhibitor (ACEI), or tumor necrosis factor alpha (TNFalpha) prior to exposure to AngII or Aldo for 0.5 h, 1 h, 2 h, and 4 h respectively. The binding activities of NF-kappaB DNA were observed by EMSA. The expression of IkappaBalpha protein was detected with Western blotting. Histochemistry was used to detect the expression of NF-kappaB p65. RT-PCR was used to detect the expression of TNFalpha mRNA in HSC-T6 cells. RESULTS: The binding activity to NF-kappaB of the liver tissues was the strongest in the Mo group, followed by the Pe and Lo groups and Nc group. The IkappaBalpha expressions in liver tissues 4 and 6 weeks after the beginning of experiment in the Pe and Lo groups were significantly stronger than that in the Mo group (both P < 0.05). 0.5 hour after the intervention of AngII the DNA binding activity of the HSCs began to increase and peaked 1 hour later and then gradually decreased. The increase of NF-kappaB activity induced by AngII could be inhibited by irbesartan, ACEI and NAC pretreatment and could not be inhibited by U0126 pretreatment. Combined action of AngII and TNFalpha significantly increased the NF-kappaB DNA binding activity. The IkappaBalpha expression began to decrease 0.5 hour after the intervention of AngII and reached the lowest value 2 hours after. The expression of IkappaBalpha protein was increased by ACEI (P < 0.05), irbesartan and NAC (both P < 0.01). EMSA showed that 0.5 hour after the intervention of Aldo the DNA binding activity began to be increased and peaked by 1 hour and then began to be decreased. NAC, but not U0126 partly inhibited the increased of NF-kappaB activity induced by Aldo. Combined action of Aldo and TNFalpha significantly increased the NF-kappaB activity. Aldo increased the expression of IkappaBalpha protein in the HSCs at different time points (all P < 0.05). 0.5 hour after the AngII intervention the IkappaBalpha protein expression began to decrease and reach the lowest value 1 hour later and then began to increase 2 hours later. the IkappaBalpha protein expression was significantly decreased in the NAC and NAC+ Aldo intervention groups (both P < 0.05). There was no significant difference in IkappaBalpha protein expression between the Aldo intervention group and U0126 + Aldo, TNFalpha, and Aldo + TNFalpha treatment groups (all P > 0.05). Before stimulation, NF-kappaB was expressed in the plasma of HSCs, however, after the stimulation of AngII or Aldo for 1 hour it was expressed in the nuclei, and then transferred from the nuclei to the plasma 4 hours after the stimulation. However, little nuclear transfer was observed after pretreatment of NAC followed by AngII or Aldo intervention. The TNFalpha mRNA expression was significantly increased in the AngII and Aldo treatment groups in comparison with the control group (both P < 0.05). The TNFalpha mRNA expression was significantly weaker in the irbesartan + AngII, NAC + AngII, and ACEI groups in comparison with the AngII group (all P < 0.05). CONCLUSION: Stimulation of NF-kappaB activity mediates hepatic fibrosis induced by intrahepatic renin-angiotensin-aldosterone system (RAAS).

[Perindopril attenuates the progression of CCl4-inducing rat hepatic fibrosis].

OBJECTIVES: The aim of the present study was to determine the effects of angiotensin-converting enzyme inhibitor, perindopril, on the progression of rat hepatic fibrosis induced by CCl4. METHODS: Male wistar rats weighting about 250g were treated with perindopril (2mg/kg, daily gavage), except for model group and control group. After 4, 6 weeks, morphological examination was based on microscopy. RT-PCR was utilized to detect gene expression of angiotensin II type 1 receptor (AT1 receptor) in the liver. Meanwhile, the protein expressions of AT1 receptor, transforming growth factor beta 1 (TGF-beta1) and platelet-derived growth factor-BB (PDGF-BB) in liver tissue were examined by Western blot. The activity of matrix metalloproteinase-2 (MMP-2) was assessed by zymography. Serum laminin (LN) and hyaluronic acid (HA) were measured using radio-immunity technique. RESULTS: RT-PCR and Western blot revealed that there was a up-regulation in AT1 receptor expression in model group compared with control group. Perindopril treatment significantly reduced mean fibrosis score, messenger RNA and protein levels of AT1 receptor, protein levels of TGF-beta1 and PDGF-BB, Serum levels of HA and LN, and MMP-2 activity. CONCLUSION: These results suggest that angiotensin II may play an important role in fibrosis of liver. Perindopril may have a inhibiting effect on CCl4-induced hepatic fibrogenesis of rat.