Activation of the mammalian target of rapamycin signaling pathway underlies a novel inhibitory role of ring finger protein 182 in ventricular remodeling after myocardial ischemia-reperfusion injury.

Myocardial ischemia-reperfusion injury (MIRI) is a major cause of cardiovascular disease, leading to mortality and disability associated with coronary occlusion worldwide. A correlation of mammalian target of rapamycin (mTOR)/nuclear factor-kappa B (NF-κB) signaling pathway has been observed with brain damage resulting from myocardial ischemia. Therefore, by establishing MIRI rat model, this study aimed to explore whether ring finger protein 182 (RNF182) regulates the mTOR signaling pathway affecting MIRI. Initially, MIRI rat model was successfully established, followed by either treatment of shRNF182 or phosphoesterase (PITE) (inhibitor of the mTOR signaling pathway). Then, the serum levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA), left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular systolic pressure (LVSP), and left ventricular end-diastolic pressure (LVEDP) were determined, followed by detection of myocardial infarct sizes and myocardial cell apoptosis. Moreover, the levels of related genes/proteins were determined to further determine the mechanisms of RNF182 in MIRI. First, RNF182 was upregulated in MIRI. Another key observation of this study was that rats with shRNF182 presented with downregulated SOD, GSH-Px, and MDA in serum, accompanied by decreased levels of LVEF, LVFS, LVSP, and LVEDP. In addition, both reduced myocardial infarct sizes and apoptosis of myocardial cells were observed after silencing RNF182. Furthermore, silencing of the RNF182 was observed to downregulate Bcl 2-associated X and cysteine proteinase 3 but upregulate mTOR, ribosome protein subunit 6 kinase 1, eukaryotic elongation factor 2, and B-cell lymphoma-2. Importantly, the effects of RNF182 silencing were reversed after PITE treatment. In conclusion, our study demonstrates that RNF182 silencing can prevent ventricular remodeling in rats after MIRI by activating the mTOR signaling pathway.

Metabolomics study of the therapeutic mechanism of Schisandra Chinensis lignans in diet-induced hyperlipidemia mice.

BACKGROUND: Schisandra, a globally distributed plant, has been widely applied for the treatment of diseases such as hyperlipidemia, fatty liver and obesity in China. In the present work, a rapid resolution liquid chromatography coupled with quadruple-time-of-flight mass spectrometry (RRLC-Q-TOF-MS)-based metabolomics was conducted to investigate the intervention effect of Schisandra chinensis lignans (SCL) on hyperlipidemia mice induced by high-fat diet (HFD). METHODS: Hyperlipidemia mice were orally administered with SCL (100 mg/kg) once a day for 4 weeks. Serum biochemistry assay of triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c) and high-density lipoprotein cholesterol (HDL-c) was conducted to confirm the treatment of SCL on lipid regulation. Metabolomics analysis on serum samples was carried out, and principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) were carried out for the pattern recognition and characteristic metabolites identification. The relative levels of critical regulatory factors of liver lipid metabolism, sterol regulatory element-binding proteins (SREBPs) and its related gene expressions were measured by quantitative real-time polymerase chain reaction (RT-PCR) for investigating the underlying mechanism. RESULTS: Oral administration of SCL significantly decreased the serum levels of TC, TG and LDL-c and increased the serum level of HDL-c in the hyperlipidemia mice, and no effect of SCL on blood lipid levels was observed in control mice. Serum samples were scattered in the PCA scores plots in response to the control, HFD and SCL group. Totally, thirteen biomarkers were identified and nine of them were recovered to the normal levels after SCL treatment. Based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis, the anti-hyperlipidemia mechanisms of SCL may be involved in the following metabolic pathways: tricarboxylic acid (TCA) cycle, synthesis of ketone body and cholesterol, choline metabolism and fatty acid metabolism. Meanwhile, SCL significantly inhibited the mRNA expression level of hepatic lipogenesis genes such as SREBP-1c, fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC), and decreased the mRNA expression of liver X receptor α (LXRα). Moreover, SCL also significantly decreased the expression level of SREBP-2 and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) in the liver of hyperlipidemia mice. CONCLUSION: Anti-hyperlipidemia effect of SCL was confirmed by both serum biochemistry and metabolomics analysis. The mechanism may be related to the down-regulation of LXRα/SREBP-1c/FAS/ACC and SREBP2/HMGCR signaling pathways.

Schisandra polysaccharide inhibits hepatic lipid accumulation by downregulating expression of SREBPs in NAFLD mice.

BACKGROUND: Hepatoprotective effects of Chinese herbal medicine Schisandra Chinensis (Schisandra) have been widely investigated. However, most studies were focused on its lignan extracts. We investigated the effects of Schisandra polysaccharide (SCP) in a mouse model of non-alcoholic fatty liver disease (NAFLD), and studied its effect on sterol regulatory element binding proteins (SREBPs) and the related genes. METHODS: The mouse model of NAFLD was established by feeding mice with a high-fat diet for 16 weeks. Effect of SCP-treatment (100 mg/kg, once daily for 12 weeks) on biochemical parameters and liver histopathology was assessed. Relative levels of sterol regulatory element-binding proteins (SREBPs) and their gene expressions were determined by quantitative real-time polymerase chain reaction and Western Blot. RESULTS: SCP significantly reduced the liver index by 12.0%. Serum levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol, alanine aminotransferase and aspartate aminotransferase were decreased by 31.3, 28.3, 42.8, 20.1 and 15.5%, respectively. Serum high-density lipoprotein cholesterol was increased by 26.9%. Further, SCP lowered hepatic TC and TG content by 27.0% and 28.3%, respectively, and alleviated fatty degeneration and necrosis of liver cells. A significant downregulation of mRNA and protein expressions of hepatic lipogenesis genes, SREBP-1c, fatty acid synthase and acetyl-CoA carboxylase, and the mRNA expression of liver X receptor α (LXRα) was observed in NAFLD mice treated with SCP. SCP also significantly reduced the hepatic expression of SREBP-2 and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). CONCLUSION: These findings demonstrate the hepatoprotective effects of SCP in a mouse model of NAFLD; the effects may be mediated via downregulation of LXRα/SREBP-1c/FAS/ACC and SREBP-2/HMGCR signaling pathways in the liver.

[Apoptosis mechanism of taxol combined with resveratrol on human laryngeal carcinoma Hep-2 cells].

Laryngeal cancer is one of the most common malignant tumors in the respiratory tumors, and its incidence ranks second highest in the respiratory tumors. Resveratrol (Res) is a kind of polyphenols, which can inhibit nucleotides can inhibit the growth of liver cancer cells, gastric cancer cells, pancreatic cells and other tumor cells by inhibiting ribonucleotide reductase in the cells. Taxol (Tax) is a kind of secondary metabolites of Taxus chinensis, which has anti-tumor activity for breast cancer, cervical cancer, ovarian cancer and other tumors by inhibiting cellular microtubule depolymerization. But at present the effects of resveratrol combined with taxol on human laryngeal carcinoma cell strain Hep-2 and their underlying molecular mechanisms are rarely reported. After human laryngeal cancer cell Hep-2 cells were processed with resveratrol (Res) and taxol (Tax), CCK-8 assay was used to evaluate the effect of these two herbs on the proliferation of cancer cells; AO/PI staining and JC-1 were used to detect Hep-1 cells apoptosis; the expression of Bax, Bcl-2, PARP, TRIB3, and XIAP genes was detected by real time quantitative PCR; the activity of caspase-3 and caspase-8 was determined with quantitative fluorescence method. The experimental results showed that compared with Tax, Res medication alone, joint group significantly enhanced inhibition of Hep-2 cells activity, decreased the dosage of Tax, increased the expression of Bax and PARP, TRIB3, reduced the expression of the Bcl-2 and XIAP, and promoted the activity of caspase-3 and caspase-8. The test results showed that compared with the single medication, combined group could significantly increase the inhibitory effect on Hep-2 cells, significantly reduce Tax dosage, increase expressions of Bax, PARP, TRIB3, reduce expressions of Bcl-2, XIAP, and promote activity of caspase-3, caspase-8. This indicated apoptosis of human laryngeal carcinoma cell strain Hep-2 may be induced with Res, Tax, and the combination of these two herbs by mitochondria pathway. It provides valuable clue for further research on combination of Res and Tax for the treatment of laryngeal cancer, and expanding the combined application of Res and Tax.

[Advance in research on endocardial fiborelastosis].

Endocardial fiborelastosis (EFE) is a common infantile myocardiosis. The pathogenesis of EFE may be associated with viral infection, genetic factors, immune factors and endocardial dysplasia. The fundamental pathological changes of EFE include hyperplasia of endocardium elastic fibers and collagen fibers. Acute EFE is a frequent type. Clinical manifestations of EFE are non-specific and children with EFE mainly present with congestive heart failure. Echocardiography is very helpful to the diagnosis of EFE. It is necessary to differentiate EFE from pneumonia complicated by acute congestive heart failure, viral myocarditis and anomalous origin of the left coronary artery. Treatment is meant to control symptoms of congestive heart failure. Patients who respond well to digitalis and have good medication compliance have a favorable prognosis.

[Clinical analysis of 68 cases of childhood dilated cardiomyopathy].

OBJECTIVE: To study the ECG features in children with dilated cardiomyopathy (DCM), and related factors for the occurrence of arrhythmia secondary to DCM. METHODS: Data from 68 children with DCM from January 1998 to March 2011 were studied. The children were classified into three groups: severe arrhythmia (n=42), non-severe arrhythmia (n=20) and non-arrhythmia (n=6). Left ventricular end diastolic diameter (LVED), left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were compared. RESULTS: Abnormal ECG results were found in all of the 68 children with DCM. Sinus tachycardia (91%) and ectopic pulsatile (86%) were common. LVED in the severe arrhythmia group (74±6 mm) was greater than that in the non-severe arrhythmia group (65±4 mm; P<0.05) and non-arrhythmia group (61±3 mm; P<0.05). LVED in the non-severe arrhythmia group was also greater than that in the non-arrhythmia group (P<0.05). LVEF and LVFS in the severe arrhythmia group were (30±11)% and (22±4)%, respectively, which were lower than those in the non-severe arrhythmia groupï¼»(37±12)% and (28±5)%, respectivelyï¼½and non-arrhythmia groupï¼»(45±9)% and (34±7)%, respectivelyï¼½(P<0.05). There were also significant differences in the LVEF and LVFS between the non-severe arrhythmia and non-arrhythmia groups (P<0.05). CONCLUSIONS: The common abnormal ECG findings are sinus tachycardia and ectopic pulsatile in children with DCM. Arrhythmia is one of the main clinical manifestations of DCM. The occurrence of arrhythmia is associated with the left ventricular size and heart function.

Relaxation Effect of Schisandra Chinensis Lignans on the Isolated Tracheal Smooth Muscle in Rats and Its Mechanism.

Schisandra chinensis (S. chinensis) is one of the core drugs used for relieving cough and asthma in traditional Chinese medicine. However, there are few basic studies on the treatment of respiratory diseases with S. chinensis in modern pharmacology, and the material basis and mechanism of its antiasthmatic effect are still unclear. Lignans are the main active components of S. chinensis. The aim of this study was to observe the relaxation effect of S. chinensis lignans (SCL) on the tracheal smooth muscle of rats by in vitro tracheal perfusion experiments, and to explore the mechanism by preincubation with L-type calcium channel blocker verapamil, four potassium channel blockers glibenclamide, tetraethylamine, 4-aminopyridine and barium chloride (BaCl2), ß-adrenoceptor blocker propranolol, nitric oxide synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME), and the cyclooxygenase inhibitor indomethacin, respectively. The results showed that SCL (0.25-1.75 mg/mL) reduced the contraction of isolated tracheal smooth muscle induced by acetylcholine, the preincubation with verapamil and glibenclamide could attenuate the relaxation effect, whereas propranolol, 4-aminopyridine, BaCl2, tetraethylamine, L-NAME, and indomethacin had no such effect. These results suggest that SCL has a significant relaxation effect on the isolated tracheal smooth muscle of rats, and the mechanism may be related to the inhibition of extracellular calcium influx and intracellular calcium release from the sarcoplasmic reticulum, as well as the activation of ATP-sensitive potassium channels. These findings may provide a pharmacological basis for the traditional use of S. chinensis to treat asthma.

Integrated Analysis of lncRNA-Mediated ceRNA Network Reveals a Prognostic Signature for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common types of malignancy and is associated with high mortality. Prior research suggests that long non-coding RNAs (lncRNAs) play a crucial role in the development of HCC. Therefore, it is necessary to identify lncRNA-associated therapeutic biomarkers to improve the accuracy of HCC prognosis. Transcriptomic data of HCC obtained from The Cancer Genome Atlas (TCGA) database were used in the present study. Differentially expressed RNAs (DERNAs), including 74 lncRNAs, 16 miRNAs, and 35 mRNAs, were identified using bioinformatics analysis. The DERNAs were subsequently used to reconstruct a competing endogenous RNA (ceRNA) network. A lncRNA signature was revealed using Cox regression analysis, including LINC00200, MIR137HG, LINC00462, AP002478.1, and HTR2A-AS1. Kaplan-Meier plot demonstrated that the lncRNA signature is highly accurate in discriminating high- and low-risk patients (P < 0.05). The area under curve (AUC) value exceeded 0.7 in both training and validation cohort, suggesting a high prognostic potential of the signature. Furthermore, multivariate Cox regression analysis indicated that both the TNM stage and the lncRNA signature could serve as independent prognostic factors for HCC (P < 0.05). Then, a nomogram comprising the TNM stage and the lncRNA signature was determined to raise the accuracy in predicting the survival of HCC patients. In the present study, we have introduced a ceRNA network that could contribute to provide a new insight into the identification of potential regulation mechanisms for the development of HCC. The five-lncRNA signature could serve as a reliable biosignature for HCC prognosis, while the nomogram possesses strong potential in clinical applications.

Effectiveness and Safety of Trabeculectomy along with Amniotic Membrane Transplantation on Glaucoma: A Systematic Review.

PURPOSE: To determine the effectiveness and safety of trabeculectomy along with amniotic membrane transplantation (AMT) for glaucoma. METHODS: This systematic review was performed using RevMan 5.3. We searched PubMed, EMBASE, and the Cochrane Library and included studies published until September 2019. The treatment group included patients with AMT and trabeculectomy (group A), and the control group had only trabeculectomy (group B). We only included randomized controlled trials. The outcomes were intraocular pressure (IOP), complete success rate, number of antiglaucoma medications, and complications. RESULTS: Five studies, including 174 eyes (87 eyes in the AMT group and 87 eyes in the control group), were eligible in this review. The parameters had no significant difference in heterogeneity between the AMT and control groups preoperatively. In the AMT group, the mean IOP was significantly lower at 3 and 12 months after operation (P < 0.0001 and P = 0.02, respectively), while the number of complete successes in the AMT group was significantly higher at 6 and 12 months (P = 0.02 and P = 0.003, respectively) compared with the control group. Complications, including a flat anterior chamber and hyphema, appeared to be decreased in the AMT group compared to the control group (P = 0.02 and P = 0.02, respectively). No differences were observed in the number of antiglaucoma medications, hypotony, encapsulated bleb, or choroidal detachment. CONCLUSION: Compared with only trabeculectomy, it is more efficient and safer to add AMT to trabeculectomy during glaucoma filtering surgery.

Protective effects of polygalasaponin F on oxidative stress and apoptosis-induced ischemic myocardial injury in neonatal rats with hypoxic-ischemic brain damage.

The aim of the present study was to evaluate the role of polygalasaponin F on ischemic myocardial injury in neonatal rats with hypoxic-ischemic brain damage. A primary in-vitro myocardial cell oxygen-glucose deprivation/reperfusion model and an in-vivo middle cerebral artery occlusion model were established. The results demonstrated that polygalasaponin F protects myocardium in hypoxic-ischemic brain injury. The mechanisms of its protective effect involved in (1) reducing oxidant stress injury, (2) reducing the apoptosis rate of myocardial cells through increasing the Bcl-2 protein level and decreasing the Cyt-C and Bax values, and (3) alleviating liver and kidney damage caused by cerebral hypoxia and ischemia via reducing the damage markers. The results of the present study may contribute toward the development of novel strategies for clinical cardioprotection with hypoxic-ischemic brain damage.

Liver cancer stem cell markers: Progression and therapeutic implications.

Cancer stem cells (CSCs) are a small subpopulation in cancer, have been proposed to be cancer-initiating cells, and have been shown to be responsible for chemotherapy resistance and cancer recurrence. The identification of CSC subpopulations inside a tumor presents a new understanding of cancer development because it implies that tumors can only be eradicated by targeting CSCs. Although advances in liver cancer detection and treatment have increased the possibility of curing the disease at early stages, unfortunately, most patients will relapse and succumb to their disease. Strategies aimed at efficiently targeting liver CSCs are becoming important for monitoring the progress of liver cancer therapy and for evaluating new therapeutic approaches. Herein, we provide a critical discussion of biological markers described in the literature regarding liver cancer stem cells and the potential of these markers to serve as therapeutic targets.

Clinical utility of the ventricular septal defect diameter to aorta root diameter ratio to predict early childhood developmental defects or lung infections in patients with perimembranous ventricular septal defect.

BACKGROUND: Ventricular septal defect (VSD) is the most frequent type of congenital heart disease. Conventional methods to evaluate VSD size and severity are both invasive and cumbersome to perform. We investigated whether the ratio between the diameter of the defect and the aortic root diameter (DVSD/DAR) would accurately reflect the degree of shunted blood and the severity of VSD in children with perimembranous VSD. METHODS: We recruited 987 children with perimembranous VSD (pmVSD) and used color Doppler echocardiography to calculate DVSD/DAR. 987 healthy children were recruited as control group. The pmVSD group was further stratified into four groups according to age (1 to 4 y) and again into four groups according to the DVSD/DAR ratio: children whose DVSD/DAR was 1/5 to <1/4, 1/4 to <1/3, 1/3 to 1/5, or 1/2 to <2/3 were assigned to groups A, B, C, and D, respectively. Height, weight, infection scores and systemic-pulmonary circulation ratio (QP/QS ratio) were compared among groups A, B, C and D. Then the relationship between the DVSD/DAR ratio and height, weight, QP/QS ratio, infection score were analysed by linear regression analysis. RESULTS: Compared to age-matched children without VSD (the controls), the mean height and weight of children in the pmVSD group were lower, and heights and weights were negatively correlated with the DVSD/DAR ratio. This ratio was significantly reduced in groups C and D compared to control group (both P<0.05). Infection scores of groups A and B were significantly higher only in the one-year-old subgroup, but were significantly higher in groups C and D for all ages compared to the control group (both P<0.05). QP/QS ratio of group C and D were higher than group A and group B (all P<0.05). Moreover, QP/QS ratio of group D for all ages were more than 2. In addition, linear regression analysis revealed that the DVSD/DAR ratio negatively correlated with height and weight and positively correlated with the QP/QS ratio and infection score. CONCLUSIONS: Our results suggest that the DVSD/DAR ratio accurately reflects the growth and pulmonary infection rates in children with pmVSD. This ratio, therefore, may be a useful additional reference index to predict the consequences of pmVSD.

[Experimental study on expression of connective tissue growth factor in viral myocarditis in mice].

OBJECTIVE: To study the expression of connective tissue growth factor (CTGF) in the myocardial tissue of mice with viral myocarditis (VMC). METHOD: Balb/c mice were infected with coxsackie virus B3 (CVB3) to establish VMC model. The mice were divided into control group (n = 50) and VMC group (n = 50). on days 4, 7, 14 and 21 after infection, heart specimens of 8 mice were randomly taken and examined after HE staining for myocardial necrosis and cellular infiltration. The area of positive Masson stained myocardium collagen fibers was measured, and collagen volume fraction (CVF) was measured. Then the level of serum creatine phosphokinase-MB (CKMB) was determined. The levels of CTGF and TGF-ß1 were detected by streptavidin peroxidase immunoperoxidase technique. Expression of CTGF and TGF-ß1 were detected with reverse transcription-polymerase chain reaction (RT-PCR). At the same time, the correlations were analyzed. RESULT: (1) The level of CKMB peaked on day 7, and decreased afterwards (455.45 ± 37.95, 606.95 ± 35.64, 573.62 ± 42.90, 308.60 ± 20.49, respectively, 4 - 21 d points), in which 4, 7, 14 d points, there was significant difference compared with control group (t = 6.144, 12.558, 11.182, respectively, P < 0.01). (2) CVF increased significantly on day 14 (8.22 ± 1.95, t = 4.486, P < 0.01) and day 21 (9.46 ± 1.87, t = 4.486, P < 0.01) in VMC group. (3) Measured by streptavidin peroxidase immunoperoxidase technique, the levels of CTGF (171.50 ± 10.25, 141.70 ± 10.863, 110.35 ± 11.051, 81.05 ± 10.190, respectively, 4 - 21 d points) and TGF-ß1 (184.90 ± 11.480, 150.25 ± 9.915, 103.50 ± 10.455, 84.15 ± 9.848, respectively, 4 - 21 d points) increased after day 4 in VMC (P < 0.01). (4) Measured by RT-PCR, the expression of CTGF mRNA and TGF-ß1 increased in VMC group, and the increase was enhanced with the disease development (P < 0.01). (5) The expression of CTGF and TGF-ß1 was positively linearly correlated (r = 0.987, P < 0.01), the expression of CTGF was negatively correlated with CVF (r = -0.901, P < 0.01), but the expression of CTGF was detected earlier than myocardial fibrosis. CONCLUSION: The increase of CTGF expression was associated with the severity of myocardial fibrosis in VMC. These results suggest that abnormal expression of CTGF may take part in the development of fibrosis in VMC.

Hydrogen sulfide induces apoptosis of pulmonary artery smooth muscle cell in rats with pulmonary hypertension induced by high pulmonary blood flow.

BACKGROUND: Abnormal apoptosis of pulmonary artery smooth muscle cells (PASMCs) is an important pathophysiological process in the pulmonary artery structural remodeling and pulmonary hypertension. We investigated possible effect of endogenous hydrogen sulfide (H2S) on apoptosis of PASMCs during the development of pulmonary hypertension induced by high pulmonary blood flow. METHODS: Thirty-nine male Sprague-Dawley rats were randomly assigned to 4-week control, 4-week shunt, 4-week shunt + propargylglycine (PPG), 11-week control, 11-week shunt and 11-week shunt + sodium hydrosulfide (NaHS) groups. Rats in 4-week shunt, 4-week shunt + PPG, 11-week shunt and 11-week shunt + NaHS groups underwent an abdominal aorta-inferior vena cava shunt. Rats in 4-week shunt + PPG group were intraperitoneally injected with PPG, an inhibitor of endogenous H2S production, for 4 weeks. Rats in 11-week shunt + NaHS group were intraperitoneally injected with NaHS, a H2S donor, for 11 weeks. Lung tissue H2S was evaluated by sulfide-sensitive electrode. Apoptosis of PASMCs were detected by terminal deoxynucleotidyl transferase mediated dUTP nick end labelling (TUNEL). Expressions of Fas, bcl-2 and caspase-3 in the PASMCs were analyzed with immunochemical staining. RESULTS: Four weeks after the shunting operation, the apoptosis of PASMCs and expression of Fas and caspase-3 were significantly decreased (P < 0.01), but expression of bcl-2 increased significantly (P < 0.01). PPG administration further inhibited the apoptosis of PASMCs, downregulated the expression of Fas and caspase-3 (P < 0.01), but increased the expression of bcl-2 (P < 0.01). After 11 weeks of shunting operation, the apoptosis of PASMCs and expression of Fas and caspase-3 were significantly decreased (P < 0.01), but expression of bcl-2 increased obviously (P < 0.01). NaHS administration significantly increased the apoptosis of PASMCs, upregulated the expression of Fas and caspase-3, but inhibited the expression of bcl-2. CONCLUSIONS: H2S induces the apoptosis of PASMCs in the development of high pulmonary blood flow-induced pulmonary hypertension by activating the Fas pathway and inhibiting the bcl-2 pathway.