Cardiotoxicity induced by fluoropyrimidine drugs in the treatment of gastrointestinal tumors.

In this editorial, we review the article published in World J Gastrointest Oncol 2019, 11: 1031-1042. We specifically focus on the occurrence, clinical characteristics, and risk factors of fluoropyrimidine drug-related cardiotoxicity in patients with gastrointestinal tumors. Despite significant advancements in diagnostic and therapeutic techniques that have reduced mortality rates associated with digestive system tumors, the incidence and mortality rates of treatment-related cardiotoxicity have been increasing, severely impacting the survival and prognosis of cancer patients. Fluoropyrimidine drugs are widely used as antimetabolites in the treatment of malignant tumors, including gastrointestinal tumors, and they represent the second largest class of drugs associated with cardiotoxicity. However, there is often a lack of awareness or understanding regarding their cardiotoxic effects and associated risks.

Prognostic factors of MINOCA and their possible mechanisms.

Objective: Despite not showing substantial stenosis of coronary arteries, Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA) presents with myocardial ischemia injury, thus having a grave prognosis and a high risk of long-term complications. This necessitates increased clinical attention and exploration of its root causes to prevent a similar crisis. Methods: Research on MINOCA is limited, especially in terms of its clinical attributes, long-term outlook, risk stratification, and prognosis-linked cardiometabolic risk factors. This review aims to fill these gaps, providing an extensive overview of clinical trials and studies on MINOCA to separate the issue from the presence of non-obstructive coronary arteries in cardiac patients. Results: It has been found that MINOCA patients still face a high risk of long-term adverse events. Due to social and physiological factors, the hospital mortality rate is higher among women, and they are also more susceptible to MINOCA. Cardiac metabolic risk factors, including disorder of glucose and lipid metabolism, as well as changes in serum CysC levels, have significant impacts on the occurrence and prognosis of MINOCA. Conclusions: Further research is still needed to fully understand the complex biological mechanisms underlying the prognostic factors of MINOCA. A profound understanding of these factors could reveal potential targets for improving prognosis, thereby indicating new strategies for managing this cardiovascular condition.

Down syndrome child with multiple heart diseases: A case report.

BACKGROUND: Down syndrome, also known as trisomy 21 syndrome, is commonly associated with congenital heart disease, and can often result in early formation of pulmonary hypertension. The development of pulmonary hypertension can result from factors such as intracardiac and macrovascular shunts, and upper airway obstruction or hypoplasia of lung tissue. Individuals with Down syndrome and congenital heart disease have a significantly lower average life expectancy, with surgical intervention being the most viable treatment option to improve longevity. CASE SUMMARY: We report the case of a 13-year-old boy with Down syndrome presenting with atrial septal defect and patent ductus arteriosus along with severe pulmonary hypertension. The electrocardiogram shows sinus rhythm and right ventricular hypertrophy. The echocardiogram shows an atrial septal defect with interrupted echo in the interatrial septum, measuring 0.813 cm in length. The patient was initially refused to be offered surgical treatment by many hospitals due to the high surgical risk and pulmonary artery resistance. After discussing the patient's diagnosis and treatment options, we ultimately recommended surgical treatment. However, the patient and their family declined this recommendation and chose to be discharged. During the follow-up period of 6 mo, there were no significant improvements or deteriorations in the patient's condition. CONCLUSION: In conclusion, this case highlights the challenges faced by individuals with Down syndrome and congenital heart disease complicated by severe pulmonary hypertension. Timely intervention and a multidisciplinary approach are crucial for improving prognosis and life expectancy. Further research is needed to enhance our understanding and develop effective interventions for this population.

Related mechanisms and research progress in straight back syndrome.

Despite the high prevalence of straight back syndrome (SBS), there is still limited research on this condition, posing challenges for effective diagnosis and treatment. The disease has been known for a long time, but there have been few related studies, which mostly consist of case reports. These studies have not been systematically summarized, making it difficult to meet the current needs of diagnosis and treatment. This article summarized the existing literature and comprehensively reviewed the diagnosis, pathogenesis, treatment, and research status of mitral valve prolapse related to SBS. We specifically emphasized the mechanisms and prognosis of SBS combined with mitral valve prolapse and discussed the latest research progress in this disease.

Efficacy and prognostic impact of Pericarpium Trichosanthis injection combined with nicorandil for intractable angina pectoris in elderly patients: A retrospective study.

BACKGROUND: Coronary artery disease (CAD) is a leading cause of global cardiovascular mortality. Refractory angina pectoris, a manifestation of CAD, requires effective drug treatments. Pericarpium Trichosanthis injection, a traditional Chinese medicine, improves cardiovascular symptoms, while nicorandil alleviates spasms and angina. Both have potential in treating CAD. AIM: To investigate the therapeutic effects of combining Pericarpium Trichosanthis injection and nicorandil in elderly patients suffering from refractory angina caused by coronary heart disease. METHODS: A retrospective analysis was conducted on the data of 130 patients diagnosed with refractory coronary heart disease. Based on the different treatment regimens administered during hospitalization, the patients were divided into a control group (58 cases) and a study group (72 cases). The control group received conventional treatment, which included aspirin, statins, and nitrate vasodilators. In addition to the conventional medication, the study group received a combination treatment of Pericarpium Trichosanthis injection and nicorandil. RESULTS: After treatment, the study group showed significantly higher left ventricular ejection fraction and cardiac output, and lower brain natriuretic peptide and C-reactive protein levels compared to the control group. The study group also exhibited improvements in angina, quality of life, exercise endurance, and lipid profiles. Multivariate logistic regression analysis revealed a relationship of lipid levels and heart function with the combined treatment. Some patients in the study group experienced headaches during treatment, but no significant adverse reactions were observed. Follow-up showed that the treatment was well-tolerated, with no drug-related adverse reactions detected. CONCLUSION: Combination of Pericarpium Trichosanthis injection and nicorandil is more effective than conventional treatment in improving symptoms and heart function in elderly patients with refractory angina pectoris.

Effects of statin therapy and treatment duration on cardiovascular disease risk in patients with nephrotic syndrome: A nested case-control study.

BACKGROUND: Although statins are the cornerstone of lipid management, hardly any of the existing studies on statin treatment of dyslipidemia in nephrotic syndrome (NS) addressed patient-centered outcomes of cardiovascular events. OBJECTIVE: To evaluate whether statin treatment impacts the outcomes of cardiovascular events in patients with NS. DESIGN: A single-center, retrospective, nested case-control study analyzed data from the First Affiliated Hospital of Army Medical University. PATIENTS: Patients diagnosed with NS from January 1, 1999, to November 30, 2014, were selected and followed up for 5 years. MEASUREMENTS AND MAIN RESULTS: A total of 2706 patients with NS were enrolled in this study cohort. Among these, 115 patients diagnosed with cardiovascular disease (CVD) at the end of the observational period and 235 CVD-free controls enrolled by 1:2 matching with gender, age, and index time were included in the study. Propensity score matching was used to match (1:1) the baseline characteristics of the cases and controls. The chi-square test was performed based on whether the patient used a statin as an exposure factor, and binary logistic regression analysis of the association between cardiovascular events and statin therapy duration was conducted. Subgroup analyses for relevant variables were also performed. The chi-square test showed that statin therapy was significantly associated with a reduction in CVD risk in patients with NS (p = 0.002). Furthermore, the risk of cardiovascular events in patients with NS decreased as the length of statin treatment increased (OR = 0.82 [95% CI 0.73-0.89], p < 0.001). CONCLUSIONS: For NS patients with dyslipidemia, statin therapy may be used to decrease CVD risk, and extended treatment was associated with more significant risk reduction.

A novel homozygous nonsense mutation in zona pellucida 1 (ZP1) causes human female empty follicle syndrome.

PURPOSE: To identify a pathogenic gene mutation in a female infertility proband characterized by empty follicle syndrome (EFS) and explore the genetic cause of EFS. METHODS: Whole exome sequencing (WES) was performed to identify the candidate pathogenic mutation. Sanger sequencing was used to validate the mutation in family members. The pathogenicity of the identified variant and its possible effects on the protein were evaluated with in silico tools. Immunofluorescence staining was used to study the possible mechanism of the mutation on affected oocyte. RESULTS: We identified a family with a novel homozygous nonsense mutation in zona pellucida 1 (ZP1) (c.199G > T [p.Glu67Ter]). Based on bioinformatics analysis, the mutation was predicted to be pathogenic. This variant generates a premature stop codon in exon 2 at the 199th nucleotide, and was inferred to result in a truncated ZP1 protein of 67 amino acids at the ZP-N1 domain. An in vitro study showed that the oocyte of the EFS proband was degenerated and the zona pellucida was absent. Additionally, the mutant ZP1 proteins were localized in the cytoplasm of the degenerated oocyte but not at the surface. CONCLUSIONS: The novel mutation in ZP1 is a genetic cause of female infertility characterized by EFS. Our finding expands the genetic spectrum for EFS and will help justify the EFS diagnosis in patients.

Intracoronary electrocardiogram during alcohol septal ablation for hypertrophic obstructive cardiomyopathy predicts myocardial injury size.

Alcohol septal ablation (ASA) has been used widely to treat patients with hypertrophic obstructive cardiomyopathy (HOCM). During the routine ASA procedure, it is difficult to detect the septal injury in real-time. The aim of the present study is to assess myocardial injury during ASA by recording intracoronary electrocardiogram (IC-ECG). From 2012 to 2015, 31 HOCM patients were treated with ASA, and IC-ECG was recorded in 21 patients successfully before and after ethanol injection. The elevation of ST-segment on IC-ECG after ethanol injection was expressed as its ratio to the level before injection or the absolute increasing value. Blood samples were collected before and after ASA for measuring changes in cardiac biomarkers. The ratio value of ST-segment elevation was positively correlated with both the amount of ethanol injected (r = 0.645, P = 0.001) and the myocardial injury size (creatine kinase-MB area under the curve (AUC) of CK-MB) (r = 0.466, P = 0.017). The absolute increment of ST-segment was also positively associated with both the amount of ethanol (r = 0.665, P = 0.001) and AUC of CK-MB (0.685, P = 0.001). However, there was no statistical correlation between the reduction of left ventricular outflow tract gradient and ST-segment elevation. Additionally no severe ASA procedure-related complications were observed in our patients. In conclusion, myocardial injury induced by ethanol injection can be assessed immediately by ST-segment elevation on IC-ECG. This study is the first to show that IC-ECG is a useful method for predicting myocardial injury during ASA in real-time.

Hypoxia increases Nrf2-induced HO-1 expression via the PI3K/Akt pathway.

Accumulating evidence indicates that transient hypoxic preconditioning improves resistance to severe hypoxia and enhances the therapeutic potential of endothelial progenitor cells (EPCs) in cell-based therapies for vascular repair and ischemic disease; however, the mechanisms underlying this process remain unclear. This study aimed to test the hypothesis that hypoxic preconditioning activates nuclear factor E2-related factor 2 (Nrf2) and expression of its target genes, resulting in improved biological function and resistance to hypoxia. Exposure to hypoxia following small interfering RNA (siRNA)-mediated knockdown of Nrf2 resulted in increased apoptosis and impaired proliferation and angiogenesis in vitro as a result of activation of nuclear translocation of Nrf2 by the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway and subsequent increase in expression of the Nrf2 target gene, heme oxygenase 1 (HO-1). Moreover, the hypoxia-induced secretion of hypoxia-inducible factor 1-alpha (HIF-1 alpha) in EPCs was inhibited by Nrf2 siRNA. In conclusion, the increased resistance to hypoxia and improved therapeutic potential of EPCs as a result of hypoxia preconditioning is mediated via the PI3K/Akt-Nrf2-HO-1 signaling pathway, and the secretion of HIF-1 alpha followed by Nrf2 activation.

Conditional expression of the type 2 angiotensin II receptor in mesenchymal stem cells inhibits neointimal formation after arterial injury.

Percutaneous coronary interventions (PCIs) are an effective treatment for obstructive coronary artery diseases. However, the procedure's success is limited by remodeling and formation of neointima. In the present study, we engineered rat mesenchymal stem cells (MSCs) to express type 2 angiotensin II receptor (AT2R) using a tetracycline-regulated system that can strictly regulate AT2R expression. We tested the ability of the modified MSCs to reduce neointima formation following arterial injury. We subjected rats to balloon injury, and reverse transcriptase polymerase chain reaction (RT-PCR) indicated no significant AT2R expression in normal rat arteries. Low expression of AT2R was observed at 28 days after balloon-induced injury. Interestingly, MSCs alone were unable to reduce neointimal hyperplasia after balloon-induced injury; after transplantation of modified MSCs, doxycycline treatment significantly upregulated neointimal AT2R expression and inhibited osteopontin mRNA expression, as well as neointimal formation. Taken together, these results suggest that transplantation of MSCs conditionally expressing AT2R could effectively suppress neointimal hyperplasia following balloon-induced injury. Therefore, MSCs with a doxycycline-controlled gene induction system may be useful for the management of arterial injury after PCI.

miR-613 regulates cholesterol efflux by targeting LXRα and ABCA1 in PPARγ activated THP-1 macrophages.

Cholesterol efflux from macrophages is a critical mechanism to prevent the development of atherosclerosis. Although PPARγ is known to be a potent sterol sensor that play a fundamental role in cholesterol metabolism, the potential effects of PPARγ responsive miRNA still need to be revealed. In this study, we found that miR-613 is inversely correlated with LXRα and ABCA1 in PPARγ activated THP-1 cells. PPARγ negatively regulates the expression of miR-613 at transcriptional level, and miR-613 suppressed LXRα and ABCA1 by targeting the 3'-UTR of their mRNAs. Furthermore, downregulation of LXRα and ABCA1 by miR-613 inhibited cholesterol efflux from PPARγ activated THP-1 macrophages. These results revealed an alternative mechanism for PPARγ regulation and provided a potential target for the treatment of cholesterol metabolic diseases.

Knockdown of Nrf2 inhibits the angiogenesis of rat cardiac micro-vascular endothelial cells under hypoxic conditions.

Angiogenesis plays an important role in myocardial repair after myocardial infarction (MI). Cardiac micro-vascular endothelial cells (CMECs) are important participants in myocardial angiogenesis processes. Recent studies have revealed that Nuclear factor-erythroid 2-related factor 2 (Nrf2), a master transcription factor of endogenous anti-oxidative defense systems, exerts cardio-protection in the cardiovascular system. However, the role of Nrf2 in the process of myocardial angiogenesis and corresponding mechanisms are not fully understood. Thus, the present study investigated the role of Nrf2 in the angiogenesis of rat CMECs to hypoxia. Trans-well assay, three-dimensional Matrigel assay were used to determine cell migration and vascular tube formation. Real-time RT-PCR, ELISA and Western blot were measured mRNA and protein expression. Here, we report that the mRNA and protein expression of Nrf2 and heme oxygenase-1(HO-1) were temporarily upregulated under hypoxic condition. Furthermore, knock down of Nrf2 significantly suppressed the migration and vascular tube formation of rat CMECs to hypoxia, Nrf2 knockdown also significantly decreased HO-1 and vascular endothelial growth factor (VEGF) expression at 48 h after transfection under hypoxic condition. Finally, transfection of CMECs with the Nrf2 over-expressing lentiviral vector upregulated HO-1 expression with a concomitant increase in cell migration and vascular tube formation induced by hypoxia, and this effect was greatly attenuated in the presence of ZnPP (a HO-1 inhibitor). Taken together, these results suggest that Nrf2 may mediate the angiogenesis of CMECs under hypoxic condition, and HO-1 is involved in regulating the angiogenesis of CMECs through Nrf2. Therefore, Nrf2 is a potent regulator of hypoxia-condition mediated angiogenesis in CMECs, which may provide a therapeutic strategy for myocardial repair after MI.

Rational design of angiotensin-I-converting enzyme inhibitory peptides by integrating in silico modeling and an in vitro assay.

Human angiotensin-I-converting enzyme (ACE) is a classic target of antihypertensive drugs and possesses a bulky, amphiphilic active pocket that is physicochemically compatible with a wide spectrum of small peptide ligands. Herein we describe a synthetic pipeline to directly optimize the atomic interactions between ACE in complex with its peptide ligands. By using this pipeline, we were able to derive thousands of peptides with potential ACE-inhibitory capacity, from which 15 structurally diverse, theoretically active samples were investigated systematically with respect to the structural, energetic, and dynamic aspects of their interactions with ACE. Subsequently, ACE-inhibitory activities of several highly promising candidates were evaluated in vitro using a standard spectrophotometric method. As might be expected, three of these candidates showed high inhibitory activities against ACE and others also significantly inhibited the enzymatic activity at low or moderate doses. Furthermore, one of these peptides, LHGPYP, was chosen for structural modification based on the details of its interaction with ACE using modeled structure data. Consequently, a Gly 3 Leu/Tyr 5 Ala double mutation on the peptide was assessed to obtain a more potent mutant LHLPAP, leading to a considerable increase in ACE-inhibitory activity (IC50 decrease from 75.4 to 4.2 µM).

Exploring the substructural space of indole-3-carboxamide derivatives binding to renin: a novel active-site spatial partitioning approach.

Renin has recently attracted much attention in the antihypertensive community, since this enzyme starts the angiotensin-converting cascade and forms the rate-limiting step in this cascade. In the present study, we describe a new method called active-site spatial partitioning (ASSP) for quantitatively characterizing the nonbonding interaction profile between renin and the substructures of indole-3-carboxamide derivatives-a novel class of achiral renin inhibitors that exhibit both high affinity and strong specificity for renin, thus blocking its active state-on the basis of structural models of protein-ligand complexes. It is shown that the ASSP-derived potential parameters are highly correlated with the experimentally measured activities of indole-3-carboxamides; the statistical models linking the parameters and activities using a sophisticated partial least squares regression technique show much promise as an effective and powerful tool for generalizing and predicting the pharmaceutical potencies and the physicochemical properties of other modified derivatives. Furthermore, by visually examining substructure-color plots generated by the ASSP procedure, it is found that the relative importance of nonbonding contributions to the recognition and binding of a ligand by renin is as follows: steric < hydrophobic < electrostatic. The polar and charged moieties that float on the surface of the ligand molecule play a critical role in conferring electrostatic stability and specificity to renin-ligand complexes, whereas the aromatic rings embedded in the core region of the ligand are the main source of hydrophobic and steric potentials that lead to substantial stabilization of the complex architecture.

PI3K and ERK/Nrf2 pathways are involved in oleanolic acid-induced heme oxygenase-1 expression in rat vascular smooth muscle cells.

Oleanolic acid (OA), a widely used plant-derived triterpenoid, has been shown to possess potent antiatherosclerotic effects, which may be associated with the induction of heme oxygenase-1 (HO-1). However, the underlying mechanisms involved in the effect of OA on HO-1 expression are unclear. In the current study, primary rat vascular smooth muscle cells (VSMCs) were exposed to OA and we found that it enhanced HO-1 expression in a concentration- and time-dependent manner, accompanied by increased HO-1 activity. VSMCs treated with OA exhibited activation of Akt, p38 and extracellular-signal-regulated kinase (ERK). Wortmannin (a PI3K inhibitor) and PD98059 (an ERK inhibitor) attenuated OA-induced HO-1 expression, whereas SB203580 (a p38 inhibitor) had no effect. The transcription factor NF-E2-related factor 2 (Nrf2) is a key regulator of HO-1 expression. OA treatment increased Nrf2 nuclear translocation, which was also inhibited by wortmannin and PD98059. Furthermore, transfection of VSMCs with the Nrf2 siRNA-expressing lentiviral vector decreased HO-1 expression induced by OA. Finally, pretreatment of VSMCs with OA remarkably reduced hydrogen peroxide-induced cell apoptotic death, and this effect was greatly attenuated in the presence of ZnPP (a HO-1 inhibitor), wortmannin or PD98059. Taken together, these results suggest that activation of Akt and ERK is required for OA-induced activation of Nrf2 followed by upregulation of HO-1 expression in VSMCs, which may confer an adaptive survival response in atherosclerosis.

Low-voltage direct-current stimulation is safe and promotes angiogenesis in rabbits with myocardial infarction.

This study evaluates safety and efficacy of low-voltage direct-current (DC) electrical stimulation of angiogenesis in rabbits with myocardial infarction (MI). Thirty Japanese rabbits were divided into treatment and control groups, and MI was induced by ligation of the left circumflex (LCX) artery. Two platinum electrodes were placed directly on the epicardium on either side of LCX artery. Low-voltage DC stimulation (4.0 V/cm, 30 min/day) was performed in the treatment group immediately after surgery until fourth week post-operatively. Cardio-electrophysiological, respiratory, hematological, blood biochemical, histopathological, immunohistochemical parameters, as well as capillary density at the marginal zone of myocardial infarct were compared between treatment and control groups. Capillary density in the treatment group (63.1 ± 2.2) was significantly higher (P < 0.01) than that in controls (45.4 ± 3.9). Overall mortality was 6.7%, and the prevalences of pneumothorax and intraoperative arrhythmia were 3.3 and 6.7%, respectively. Transient hypotension, anemia, leukocytosis, hypoxemia, and a slight increase in myocardial enzymes levels were observed in both groups. Regarding electrical stimulation, no adverse reactions except a minor infiltration of inflammatory cells and mild degeneration were observed in the myocardium. It was, therefore, concluded that low-voltage DC stimulation in the MI rabbits was not only safe but also effective in promoting angiogenesis in the myocardium.

[Efficacy of stents coated with antibody against CD105 on preventing restenosis and thrombosis in minipigs].

OBJECTIVE: Novel stents loaded with antibody against CD105 were analyzed for their potential to limit coronary neointima formation and to accelerate endothelialization by attracting activated endothelial cell. METHODS: Thirty Stents coated with antibody against CD105, thirty unloaded polymer, and thirty bare metal stents were deployed in 90 coronary arteries of 30 minipigs. Oral aspirin (300 mg before operation and 100 mg post operation) and clopidogrel (300 mg before operation and 75 mg post operation) were orally administrated. Coronary artery quantitative analysis was completed by coronary arteriography, the vascular endothelium changes were observed under scanning electron microscope and the vascular morphological changes were observed under light microscope 7 and 14 days after operation. RESULTS: Complete procedural and angiographic success was achieved in all 30 minipigs. There were no major adverse cardiac and cerebrovascular events. At 7 days, there was no difference for mean neointimal area and percent area stenosis among various groups. At 14 days, endothelialization scores were significantly higher in the CD105 antibody-loaded stents and bare metal stents group than in sirolimus-eluting stents group (1.78 ± 0.49, 1.50 ± 0.67 vs. 1.08 ± 0.29, all P < 0.05), mean percent area stenosis in the CD105 antibody-loaded stents, sirolimus-eluting stents group were less than that in bare metal stents group [(23.8 ± 4)%, (24.2 ± 2)% vs. (38.0 ± 3)%, all P < 0.05], mean angiographic late luminal loss in the CD105 antibody-loaded stents, sirolimus-eluting stents group were less than that in bare metal stents group [(0.29 ± 0.28) mm, (0.28 ± 0.02) mm vs. (0.41 ± 0.01) mm, all P < 0.05]. There was no difference for mean percent area stenosis in the CD105 antibody-loaded stents and sirolimus-eluting stents group. The mean neointimal area in the CD105 antibody-loaded stents, and sirolimus-eluting stents group were less than that in bare metal stents group [(0.88 ± 0.08) mm(2), (0.89 ± 0.12mm)(2) vs. (1.00 ± 0.14) mm(2), all P < 0.05] and there was no difference for the mean neointimal area in the CD105 antibody-loaded stents and sirolimus-eluting stents group. At 7 and 14 days, there was no difference for the injury score and the inflammation score among various groups, scanning electron microscopy evidenced enhanced endothelial coverage on CD105 antibody-loaded stents compared to sirolimus-eluting stents group. CONCLUSION: Stent coated with antibody against CD105 could effectively reduce in-stent restenosis and accelerate endothelialization in the minipigs.

Electrical stimulation inhibits neointimal hyperplasia after abdominal aorta balloon injury through the PTEN/p27Kip1 pathway.

Electric fields (EFs) exert biological effects on promoting wound healing by facilitating cell division, cell proliferation, and cell directional migration toward the wound. In this study, we examined the inhibitory effect of direct-current (DC) EFs on the formation of neointimal hyperplasia and the possible mechanism in an abdominal aorta balloon injury rabbit model. Sixty rabbits were divided into normal, control, and experimental groups. After establishment of the abdominal aorta balloon injury model, electrodes were implanted into the bilateral psoas major muscle in control and experimental groups. Only the experimental group received electric stimulation (EFs applied at 3 or 4 V/cm for 30 min/day) for 1, 2, and 4 weeks, respectively. Neointimal hyperplasia of the abdominal aorta and proliferation of vascular smooth muscle cells (VSMCs) were measured. Expressions of collagen, p27(Kip1), and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) were detected. Results showed that the ratio of the tunica intima area to the tunica media area, the expression of type-I collagen in the neointimal, and the proliferating cell nuclear antigen index in experimental groups were significantly less than those in control groups 2 weeks post-operation (P< 0.01). Expressions of p27(Kip1) and PTEN were increased in experimental groups compared with control groups (P< 0.01). In conclusion, our results suggested that the application of DC EFs could inhibit neointimal hyperplasia and reduce collagen expression after abdominal aorta balloon injury. This was probably induced by upregulation of PTEN/p27(Kip1) expression, thereby inhibiting VSMC proliferation.

Conditional expression of type 2 angiotensin II receptor in rat vascular smooth muscle cells reveals the interplay of the angiotensin system in matrix metalloproteinase 2 expression and vascular remodeling.

Angiotensin II is well implicated in neointimal proliferation and the resulting restenosis, however, the mechanisms involved remain unclear. The type 2 angiotensin II (AT2) receptor, largely unexpressed in the adult vasculature, however, appears at significant levels after vascular injury. To investigate the specific contribution of AT2 receptor and the interplay of the angiotensin system to neointima, we engineered rat vascular smooth muscle cells (VSMCs) to express the AT2 receptor in a tetracycline-regulated system. Several VSMC clones resistant to both hygromycin and G418 were selected, many of which showed high, but regulatable levels of AT2R expression within 48 h of doxycycline (Dox) exposure. In untransfected VSMCs and stable transfectants with no AT2R induction, Ang II significantly increased the expression of matrix metalloproteinase 2 (MMP-2), which is linked to neointimal growth. However, induction of AT2R by Dox addition markedly decreased MMP-2 levels (P<0.01) and this downregulation was further promoted by CV-11974, a specific antagonist of AT1 receptor. In contrast, the PD123319 compound, which selectively curtails the AT2 receptor, reversed the inhibition caused by CV-11974. We conclude that Ang II enhances the MMP-2 expression via AT1R, and that enforces AT2R inhibited the same. These data confirm that AT2R functions to downregulate the effects elicited by Ang II + AT1R signaling and point to the role of MMP and extracellular matrix in vascular injury. The findings provide fresh experimental approaches to prevent or control restenosis through transduction of VSMCs expressing optimal levels of AT2R.

Clinical efficiency and safety analysis of transcatheter closure of multiple atrial septal defects in adults.

BACKGROUND: Transcatheter closure of atrial septal defects (ASDs) is currently a reliable alternative to surgery, even though challenging in patients with multiple ASDs. HYPOTHESIS: The aim of this study was to evaluate the clinical efficiency and safety of transcatheter closure in multiple ASDs. METHODS: Multiple ASDs were diagnosed by transthoracic echocardiography (TTE) or transesophageal echocardiography (TEE). The occlusive condition and distance between 2 adjacent ASDs were measured by TTE examination. Then, the number and size of the occluder(s) was determined. TTE examinations were performed after transcatheter closure as follow-up. RESULTS: The transcatheter procedure was successful in 15 patients with multiple ASDs, using a single occluder in 9 patients and 2 occluders in the remaining 6 patients. Overall, 21 ASD occluders were implanted. During a follow-up period of 6 mo to 5 y, a slight residual shunt was found in 1 patient without any symptoms; a moderate residual shunt was identified at the inferior vena cava and the occluder was removed by surgery 1 mo after procedure. Other complications, including endocarditis, arrhythmia, thromboembolism, and atrioventricular valve damage were not recorded in any of the 15 patients during the follow-up period. CONCLUSION: Transcatheter closure of multiple ASDs is safe and efficient. Two occluders are necessary for the distance of 2 ASDs more than 7 mm, and a single occluder is sufficient for those 7 mm or less.