Angiotensin-converting enzyme - human amniotic mesenchymal stem cells improve pulmonary vascular remodeling in rats with pulmonary hypertension by promoting angiogenesis and counteracting inflammation.

OBJECTIVES: Human Amniotic Mesenchymal Stem Cells (hAMSCs) have strong multidirectional differentiation ability. Studies have found that transfection of target genes into target cells by lentivirus can enhance the differentiation potential of the cells. Angiotensin-Converting Enzyme 2 (ACE2) was found to improve vascular remodeling. Research is lacking on ACE2-hAMSCs. Therefore, this study aimed to investigate the ability to improve pulmonary arterial hypertension using ACE2-hAMSCs. METHODS: Lentiviruses overexpressing ACE2 were mixed with hAMSCs. Then, ACE2-hAMSCs and hAMSCs with good growth in logarithmic growth phase were collected. We detected their migration and angiogenesis. RT-qPCR technology was used to detect the expression levels of genes related to angiogenesis, and inflammation in the two cell lines, and western-blotting was used to detect the expression levels of ACE2. As an animal study, 21 rats were randomly divided into four different groups. Right heart hypertrophy, pulmonary angiogenesis, and serum inflammatory factors were measured before dissection. H&E staining was used to observe the inflammatory infiltration of lung tissues. RESULTS: The migration and angiogenesis of ACE2-hAMSCs were strongerthan that of hAMSCs alone. The expressions of genes in ACE2-hAMSCs were higher, and the expression of ACE2 protein in ACE2-hAMSCs was less. H&E staining showed that the inflammatory infilration of lung tissue in ACE2-hAMSCs groups was significantly improved. In addition, the ACE2-hAMSCs group had stronger pro-angiogenesis and anti-inflammatory effects. CONCLUSION: These results suggest that ACE2-hAMSCs can repair pulmonary vascular endothelial cell injury caused by pulmonary hypertension by promoting angiogenesis and anti-inflammatory ability. This shows that ACE2-hAMSCs have stronger ability to improve pulmonary vascular remodeling than hAMSCs alone.

A case of acute myelogenous leukemia characterized by arterial and venous thrombosis.

Acute myelogenous leukemia (AML) is a malignant disease of the hematopoietic system, characterized by features of bone marrow insufficiency and organ infiltration by leukemic cells. Venous thrombosis in AML patients is uncommon, compared to bleeding; therefore in patients with AML, simultaneous occurrence of venous and arterial thrombosis is a rather rare presentation. We reported an unusual case of anti-phospholipid antibody syndrome secondary to AML characterized by venous and arterial thrombosis. A 70-year-old man with deep venous thrombosis (DVT) of the left leg confirmed by Doppler was seen in our clinic. During treatment with a Vitamin K antagonist (3 mg daily of Warfarin) and a low molecular weight heparin (LMWH), he developed an acute pulmonary embolism and an acute inferior wall ST elevation myocardial infarction (STEMI), a result of right coronary artery embolism. His full blood count showed leukocytosis and thrombocytopenia. Lupus anticoagulant and anti-cardiolipin antibodies were positive. A bone marrow aspirate test showed results consistent with AML (FAB class M1). A diagnosis of antiphospholipid antibody syndrome secondary to AML characterized by coronary artery embolism, pulmonary embolism and left leg DVT was eventually established. He received anticoagulation with a low dose of warfarin after refusing chemotherapy. He however died of cerebral hemorrhage despite the fact that the INR was in the normal therapeutic range. It is challenging to anticoagulated AML patients complicated by multiple vascular thromboses and thrombocytopenia.

Association between high blood pressure and long term cardiovascular events in young adults: systematic review and meta-analysis.

OBJECTIVE: To evaluate and quantify the future risk of cardiovascular events in young adults with high blood pressure. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, and Web of Science were searched from inception to 6 March 2020. Relative risks were pooled using a random effects model and expressed with 95% confidence intervals. Absolute risk difference was calculated. Dose-response relations between blood pressure and individual outcomes were assessed by a restricted cubic spline model. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Studies were selected that investigated the adverse outcomes of adults aged 18-45 with raised blood pressure. The primary study outcome was a composite of total cardiovascular events. Coronary heart disease, stroke, and all cause mortality were examined as secondary outcomes. RESULTS: Seventeen observational cohorts consisting of approximately 4.5 million young adults were included in the analysis. The average follow-up was 14.7 years. Young adults with normal blood pressure had increased risk of cardiovascular events compared with those with optimal blood pressure (relative risk 1.19, 95% confidence interval 1.08 to 1.31; risk difference 0.37, 95% confidence interval 0.16 to 0.61 per 1000 person years). A graded, progressive association was found between blood pressure categories and increased risk of cardiovascular events (high normal blood pressure: relative risk 1.35, 95% confidence interval 1.22 to 1.49; risk difference 0.69, 95% confidence interval 0.43 to 0.97 per 1000 person years; grade 1 hypertension: 1.92, 1.68 to 2.19; 1.81, 1.34 to 2.34; grade 2 hypertension: 3.15, 2.31 to 4.29; 4.24, 2.58 to 6.48). Similar results were observed for coronary heart disease and stroke. Generally, the population attributable fraction for cardiovascular events associated with raised blood pressure was 23.8% (95% confidence interval 17.9% to 28.8%). The number needed to treat for one year to prevent one cardiovascular event was estimated at 2672 (95% confidence interval 1639 to 6250) for participants with normal blood pressure, 1450 (1031 to 2326) for those with high normal blood pressure, 552 (427 to 746) for those with grade 1 hypertension, and 236 (154 to 388) for those with grade 2 hypertension. CONCLUSIONS: Young adults with raised blood pressure might have a slightly increased risk of cardiovascular events in later life. Because the evidence for blood pressure lowering is limited, active interventions should be cautious and warrant further investigation.

Transfer of human hepatocyte growth factor reduces inflammation and prevents pulmonary arterial remodeling in monocrotaline-induced.

Inflammation and endothelial dysfunction contribute to the pathogenesis and development of pulmonary arterial hypertension (PAH). This study was to investigate the therapeutic effect of human hepatocyte growth factor (HGF) gene transfer on monocrotaline (MCT) induced PAH rat models. PAH was induced by injecting MCT for 4 weeks. The rats were randomly assigned to phosphate buffered saline control group, MCT group, and HGF treatment group. After 2 weeks of induction, measures of mean pulmonary artery pressure (mPAP), weight ratio of the RV to the LV plus septum, percent wall thickness index (TI) and area index (AI) were significantly increased in MCT-group and HGF treatment-group compared with those in control group (P < 0.05). Those measurements in MCT-group were significantly higher than those in HGF treatment-group (P < 0.05). IL-6 significantly decreased in HGF treatment-group compared with MCT-group, but higher than that of control group (all P < 0.05). IL-10 in HGF treatment-group significantly increased compared with MCT-group, but lower than that of control group (all P < 0.05). Endothelial microparticles (EMP) started to decrease in the HGF treatment-group 3 days after treatment and was most significant after 1 and 2 weeks of treatment (all P < 0.05). Our results showed that transfer of human HGF may attenuate the inflammatory cell infiltrate, reduce the expression of inflammatory factors, and those effects are possibly due to the inhibition of EMP production which may decrease pulmonary vascular wall damage in PAH.

Proangiogenic compositions of microvesicles derived from human umbilical cord mesenchymal stem cells.

INTRODUCTION & OBJECTIVE: Microvesicles (MVs) derived from mesenchymal stem cells (MSCs) have been shown to promote angiogenesis. This study was aimed to shed a light on the mechanisms by analyzing the angiogenesis-promoting compositions of MSC-MVs. Also we try to figure out the impact of hypoxia on angiogenesis. METHODS: MVs were isolated from the culture supernatants of MSCs under hypoxia/normoxia and serum-deprivation condition. The morphological features of MVs were revealed by an electron microscope and the origin of the MVs was identified by a bead-bound assay. An antibody array was used to analyze the expression of angiogenic cytokines from MVs and the parent MSCs as well. The major candidate factors were screened and the results were validated by immune blotting. RESULTS: MSC-MVs were around 80 nm in diameter. They expressed CD29, CD44, and CD73, but not CD31 and CD45. Antibody array showed that both MSCs and MVs expressed many angiogenesis-promoting biomolecules, including interleukin-6 (IL-6), basic fibroblast growth factors (bFGF), and recptor of urokinase-type plasminogen activator (UPAR). MSC-MVs contained angiogenin, vascular endothelial growth factor (VEGF), monocyte chemotactic protein-1 (MCP-1) and the receptor-2 for vascular endothelial growth factor at higher levels than the parent MSCs. Under hypoxic condition most cytokines were expressed in greater quantity than normoxic in MSCs while in MVs there was no significant difference between hypoxic and normoxic conditions except UPAR, Angiogenin, VEGF, IGF, Tie-2/TEK, and IL-6 which were higher in MVs under hypoxic conditions than those in normoxic condition. CONCLUSION: Upon serum-deprivation condition, MSCs could secrete MVs that contain a variety of factors contributing to their angiogenesis-promoting function. And among them, Angiogenin, VEGF, MCP-1, VEGF R2 might be of greater importance than the other cytokines. Also UPAR, Angiogenin, VEGF, IGF, Tie-2/TEK, IL-6 might be responsible for hypoxia-augmented proangiogenic effects of MVs.