Long-chain noncoding RNA GAS5 mediates oxidative stress in cardiac microvascular endothelial cells injury.

This study is performed to figure out the role of long-chain noncoding RNA growth-arrest specific transcript 5 (GAS5) in homocysteine (HCY)-induced cardiac microvascular endothelial cells (CMECs) injury. CMECs were cultured and the model of CMECs injury was established by coincubation with HCY. To construct stable overexpression of GAS5 cells, the expression of GAS5, microRNA-33a-5p (miR-33a-5p) and ATP-binding cassette transporter A1 (ABCA1), and biological characteristics of cells were determined. The messenger RNA (mRNA) level and secretion of vascular endothelial growth factor (VEGF), activity of reactive oxygen species (ROS) and superoxide dismutase (SOD), and the content of malondialdehyde (MDA) were measured. The binding site between GAS5 and miR-33a-5p and between miR-33a-5p and ABCA1 was verified. CMECs were successfully cultured. Reduction of GAS5 expression and ABCA1 expression together with increased expression of miR-33a-5p was found in CMECs induced by HCY. After overexpression of GAS5, there showed increased proliferative activity, decreased cell apoptosis rate and apoptosis index, enhanced cell migration ability, increased number of lumen formation, increased mRNA expression of VEGF in cells and the secretion in the supernatant, decreased activity of ROS and SOD in cells, and decreased content of ROS in cells. miR-33a-5p could promote the enrichment of GAS5 and ABCA1 was the direct target gene of miR-33a-5p. Our study suggests that the low expression of GAS5 was observed in HCY-induced CMECs injury, and the upregulation of GAS5 could attenuate HCY-induced CMECs injury by mediating oxidative stress, and its mechanism is related to the upregulation of ABCA1 expression by competitively binding with miR-33a-5p.

Young human PRP promotes the rejuvenation of aged bone marrow mesenchymal stem cells and the therapeutic effect on ischemic heart disease.

Bone marrow mesenchymal stem cell (BMSC) transplantation is an effective treatment for ischemic heart disease, but its effectiveness is limited in aging populations due to decreased viability and injury resistance of autologous BMSCs. The purpose of this study was to compare the differences between platelet-rich plasma (PRP) derived from young and aged donors, and to investigate whether it is possible to enhance the viability of elderly human BMSCs (hBMSCs) using PRP, and to apply the rejuvenated hBMSCs for the treatment of ischemia. The key growth factors in PRP, including IGF-1, EGF, and PDGF-BB, were found to have significant differences between young and old individuals. Our results showed that PRP could enhance the proliferation, cloning, and rejuvenation of aged hBMSCs, with a superior effect observed when using PRP derived from younger donors. In the SD rat infarct model, the application of hBMSCs optimized with PRP resulted in a smaller infarct area compared to the control group (NC-Old). Specifically, the infarct area in the group treated with hBMSCs cultured with PRP from young donors (YPRP-Old) was smaller than that in the group treated with PRP from older donors (OPRP-Old). The survival rate of hBMSCs after transplantation, the number of neovascularization in the infarct area of SD rats and the recovery of cardiac function were all higher in the YPRP-Old group than the OPRP-Old group, and both groups were better than the group treated with aged hBMSCs alone. In conclusion, PRP may provide a new stem cell transplantation therapy option for ischemic diseases.

Cardioprotective effect of ultrasound-targeted destruction of Sirt3-loaded cationic microbubbles in a large animal model of pathological cardiac hypertrophy.

Pathological cardiac hypertrophy occurs in response to numerous increased afterload stimuli and precedes irreversible heart failure (HF). Therefore, therapies that ameliorate pathological cardiac hypertrophy are urgently required. Sirtuin 3 (Sirt3) is a main member of histone deacetylase class III and is a crucial anti-oxidative stress agent. Therapeutically enhancing the Sirt3 transfection efficiency in the heart would broaden the potential clinical application of Sirt3. Ultrasound-targeted microbubble destruction (UTMD) is a prospective, noninvasive, repeatable, and targeted gene delivery technique. In the present study, we explored the potential and safety of UTMD as a delivery tool for Sirt3 in hypertrophic heart tissues using adult male Bama miniature pigs. Pigs were subjected to ear vein delivery of human Sirt3 together with UTMD of cationic microbubbles (CMBs). Fluorescence imaging, western blotting, and quantitative real-time PCR revealed that the targeted destruction of ultrasonic CMBs in cardiac tissues greatly boosted Sirt3 delivery. Overexpression of Sirt3 ameliorated oxidative stress and partially improved the diastolic function and prevented the apoptosis and profibrotic response. Lastly, our data revealed that Sirt3 may regulate the potential transcription of catalase and MnSOD through Foxo3a. Combining the advantages of ultrasound CMBs with preclinical hypertrophy large animal models for gene delivery, we established a classical hypertrophy model as well as a strategy for the targeted delivery of genes to hypertrophic heart tissues. Since oxidative stress, fibrosis and apoptosis are indispensable in the evolution of cardiac hypertrophy and heart failure, our findings suggest that Sirt3 is a promising therapeutic option for these diseases. STATEMENT OF SIGNIFICANCE: Pathological cardiac hypertrophy is a central prepathology of heart failure and is seen to eventually precede it. Feasible targets that may prevent or reverse disease progression are scarce and urgently needed. In this study, we developed surface-filled lipid octafluoropropane gas core cationic microbubbles that could target the release of human Sirt3 reactivating the endogenous Sirt3 in hypertrophic hearts and protect against oxidative stress in a pig model of cardiac hypertrophy induced by aortic banding. Sirt3-CMBs may enhance cardiac diastolic function and ameliorate fibrosis and apoptosis. Our work provides a classical cationic lipid-based, UTMD-mediated Sirt3 delivery system for the treatment of Sirt3 in patients with established cardiac hypertrophy, as well as a promising therapeutic target to combat pathological cardiac hypertrophy.

Association of Serum Homocysteine with Cardiovascular and All-Cause Mortality in Adults with Diabetes: A Prospective Cohort Study.

Background: Homocysteine (Hcy) was implicated in oxidative stress and diabetes biologically. However, the clinical evidence on the link between Hcy level and diabetes is limited and controversial. This study is aimed at investigating the association of serum Hcy with all-cause and cardiovascular mortality in diabetic patients. Methods: Serum Hcy was measured among 2,286 adults with type 2 diabetes in NHANES 1999-2006. Cox proportional hazard regression was used to estimate hazard ratios (HR) and 95% CIs for the association of Hcy with all-cause and cause-specific mortality. Results: Over a median follow-up of 11.0 (interquartile range, 8.9-13.4) years, 952 of the 2286 patients with diabetes died, covering 269 (28.3%) cardiovascular deaths and 144 (15.2%) cancer deaths. Restricted cubic spline showed the linear relationship between Hcy and all-cause mortality risk. After multivariate adjustment, higher serum Hcy levels were independently associated with increased risk of all-cause and cardiovascular mortality. Compared with participants in the bottom tertile of Hcy, the multivariate-adjusted HRs and 95% CI for participants in the top quartile were 2.33 (1.64-3.30) for all-cause mortality (p trend < 0.001), 2.24 (1.22-4.10) for CVD mortality (p trend = 0.017), and 2.05 (0.90-4.69) for cancer mortality (p trend = 0.096). The association with total mortality was especially stronger among patients with albuminuria. Serum Hcy significantly improved reclassification for 10-year mortality in diabetic patients (net reclassification index = 0.253 and integrated discrimination improvement = 0.011). Conclusions: Serum Hcy was associated with risks of all-cause and cardiovascular mortality in diabetic adults. Our results suggested that Hcy was a promising biomarker in risk stratification among diabetic patients.

Disentangling Large- and Small-Scale Abiotic and Biotic Factors Shaping Soil Microbial Communities in an Alpine Cushion Plant System.

Microorganisms play a crucial role in biogeochemical cycles and ecosystem processes, but the key factors driving microbial community structure are poorly understood, particularly in alpine environments. In this study, we aim to disentangle the relative contribution of abiotic and biotic factors shaping bacterial and fungal community structure at large and small spatial and integration scales in an alpine system dominated by a stress-tolerant cushion species Thylacospermum ceaspitosum. These effects were assessed in two mountain ranges of northwest China and for two contrasting phenotypes of the cushion species inhabiting two different microtopographic positions. The large- and small-scale abiotic effects include the site and microhabitat effects, respectively, while the large- and small-scale biotic effects include the effects of cushion presence and cushion phenotype, respectively. Soil microbial communities were characterized by Illumina Miseq sequencing. Uni- and multivariate statistics were used to test the effects of abiotic and biotic factors at both scales. Results indicated that the site effect representing the soil pH and abiotic hydrothermal conditions mainly affected bacterial community structure, whereas fungal community structure was mainly affected by biotic factors with an equal contribution of cushion presence and cushion phenotype effects. Future studies should analyze the direct factors contributing to shaping microbial community structure in particular of the cushion phenotypes.

Tolerance between non-resource stress and an invader determines competition intensity and importance in an invaded estuary.

The competition-to-stress hypothesis suggests that some competitively disadvantaged species are excluded from higher inundation estuaries due to abiotic stress (high flooding level) and from lower inundation estuaries by competition. How abiotic and biotic stress interactions affect plant growth and whether competition intensity and importance are stable along environmental gradients is a controversial subject. We explored the influence of two factors, and we clarified that inundation stress and invasion competition are the main reasons leading to the traits exhibited by target plant Suaeda salsa and population presence changes. Our results indicated that when the flooding height exceeded 13.4 cm, the S. salsa mortality rate was 90%-100%. At the lower flooding heights (<13.4 cm), the S. salsa mortality rate when neighboring plants were present was 77.7%-100%, whereas, without neighbors it was 30.9%-83.7%. The invader Spartina alterniflora inhibited S. salsa plant height by 48%-77%, whereas the S. alterniflora inhibited S. salsa density by 11%-98% and reduced its biomass by 50.5%-90.1%. The changes in competition intensity and importance showed that the S. alterniflora had a distinct impact from the early germinant period to growing period (from May to July), finally stable no differences along the flooding height in the maturity period. At the same flooding level, the analysis of above and belowground competition by S. alterniflora showed that aboveground and belowground competition are the main causes of individual S. salsa inhibition. Our results confirm the competitive stress hypothesis, which is that competition shapes individual traits and population presence in the context of abiotic stress. This conclusion can guide the management and protection of native plants under biological invasion in a stressful environment.

Trait and density responses of Spartina alterniflora to inundation in the Yellow River Delta, China.

Understanding plant traits in response to physical stress has been an important issue in the study of coastal saltmarshes. For plants that reproduce both sexually and asexually, whether and how seedlings (sexual reproduction) and clonal ramets (asexual reproduction) may differentially respond to tidal inundation is still unclear. We investigated the growth and morphology of sexual and asexual propagules of an exotic saltmarsh plant (Spartina alterniflora) along a gradient of tidal submergence in the Yellow River Delta. Our results showed that the density, height and basal diameter of clonal ramets or sexual seedlings increased with tidal inundation. The patch amplification edge clonal ramets are superior than patch center plants. The differences response of plants to tidal inundation highlight the sensitivity of S. alterniflora to future tidal regime shifts and can help predict and evaluate the impacts of changes in inundation conditions due to sea level rise, coastal erosion and human activities.