ABSTRACT
Coronary artery bypass grafting (CABG) is an effective treatment for coronary heart disease, with vascular transplantation as the key procedure. Intimal hyperplasia (IH) gradually leads to vascular stenosis, seriously affecting the curative effect of CABG. Mesenchymal stem cells (MSCs) were used to alleviate IH, but the effect was not satisfactory. This work aimed to investigate whether lncRNA MIR155HG could improve the efficacy of MSCs in the treatment of IH and to elucidate the role of the competing endogenous RNA (ceRNA). The effect of MIR155HG on MSCs function was investigated, while the proteins involved were assessed. IH was detected by HE and Van Gieson staining. miRNAs as the target of lncRNA were selected by bioinformatics analysis. qRT-PCR and dual-luciferase reporter assay were performed to verify the binding sites of lncRNA-miRNA. The apoptosis, Elisa and tube formation assay revealed the effect of ceRNA on the endothelial protection of MIR155HG-MSCs. We observed that MIR155HG improved the effect of MSCs on IH by promoting viability and migration. MIR155HG worked as a sponge for miR-205. MIR155HG/miR-205 significantly improved the function of MSCs, avoiding apoptosis and inducing angiogenesis. The improved therapeutic effects of MSCs on IH might be due to the ceRNA role of MIR155HG/miR-205.
Subject(s)
Apoptosis , Hyperplasia , Mesenchymal Stem Cells , MicroRNAs , RNA, Long Noncoding , MicroRNAs/genetics , MicroRNAs/metabolism , Mesenchymal Stem Cells/metabolism , Humans , RNA, Long Noncoding/genetics , Apoptosis/genetics , Cell Movement/genetics , Animals , Mesenchymal Stem Cell Transplantation/methods , Tunica Intima/pathology , Tunica Intima/metabolism , Gene Expression Regulation , Cell Proliferation/genetics , Male , Cell Survival/genetics , RNA, Competitive EndogenousABSTRACT
BACKGROUND: The mesenchymal stem cells (MSCs) were used to repair tissue injury. However, the treatment effect was not satisfactory. We investigated whether lncRNA MIR155HG could promote survival and migration of MSCs under oxidative stress, which mimics in vivo environments. Furthermore, we studied the protective effect of exosomes secreted by MSCs transfected with MIR155HG on endothelial cells. This study aimed to determine whether exploiting MSCs and exosomes modified with lncRNA MIR155HG would exert synergistic therapeutic effect to attenuate vein graft intimal hyperplasia more effectively. METHODS: Lentivirus containing lncRNA MIR155HG overexpressing vector was packaged and used to infect MSCs. Then, CCK-8 assay, flow cytometry, Transwell assay, and Elisa assay were used to assess the functional changes of MSCs with overexpressed MIR155HG (OE-MSCs). Furthermore, the associated pathways were screened by Western blot. MIR155HG-MSCs-derived exosomes (OE-exo) were collected and co-cultured with human umbilicus vein endothelial cell (HUVEC). We validated the protective effect of OE-exo on HUVEC. In vivo, both MSCs and exosomes modified with MIR155HG were injected into a vein graft rat model via tail vein. We observed MSCs homing and intimal hyperplasia of vein graft using a fluorescent microscope and histological stain. RESULTS: Our study found that lncRNA MIR155HG promoted proliferation, migration, and anti-apoptosis of MSCs. NF-κB pathway took part in the regulation process induced by MIR155HG. OE-exo could enhance the activity and healing ability of HUVEC and reduce apoptosis. In vivo, OE-MSCs had a higher rate of homing to vascular endothelium. The combined treatment with OE-MSCs and OE-exo protected vascular endothelial integrity, reduced inflammatory cell proliferation, and significantly attenuated intimal hyperplasia of vein graft. CONCLUSION: LncRNA MIR155HG could promote the survival and activity of MSCs, and reduce the apoptosis of HUVECs using exosome delivery. Exploiting MSCs and exosomes modified with MIR155HG could attenuate vein graft intimal hyperplasia more effectively and maximize the surgical effect.
Subject(s)
Exosomes , Mesenchymal Stem Cells , RNA, Long Noncoding , Humans , Rats , Animals , Exosomes/metabolism , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Hyperplasia/metabolism , Mesenchymal Stem Cells/metabolism , Cell Proliferation , Human Umbilical Vein Endothelial CellsABSTRACT
BACKGROUND: Visit-to-visit variability in blood pressure (BP) was demonstrated to correlate with cardiovascular events independent of mean BP. The goal of the present study was to investigate the correlation of visit-to-visit BP variability with artery stiffness and myocardial perfusion in on-treated hypertensive patients. METHODS: BP was measured in 271 hypertensive patients at every visit over the course of the antihypertensive treatment, and the standard deviation (SD), coefficient of variation (CV), maximum, and minimum in serial BP were calculated. Non-invasive pulse wave analysis was performed in all patients. RESULTS: Compared with baseline, carotid-femoral pulse wave velocity (cfPWV), aortic augmentation index (Aix) and Aix adjusted to a "standard heart rate" of 75 beats/min (Aix@HR75) were markedly declined, and sub-endocardial viability ratio (SEVR) was obviously increased in each group (p < 0.001). The changes of cfPWV, SEVR, Aix and Aix@HR75 in patients with lower SD of systolic blood pressure (SBP) were significantly greater than those in patients with higher SD of SBP. And the changes were statistically correlated with both SD and CV of serial SBP during follow-up, even after adjusted for mean SBP and mean diastolic blood pressure (DBP). CONCLUSION: Visit-to-visit SBP variability is independently correlated with changes of artery stiffness and myocardial perfusion in on-treated hypertensive patients.
Subject(s)
Antihypertensive Agents/therapeutic use , Blood Pressure/drug effects , Hypertension/drug therapy , Vascular Stiffness/drug effects , Aged , Blood Flow Velocity/drug effects , Blood Flow Velocity/physiology , Blood Pressure/physiology , Blood Pressure Determination/methods , Carotid Arteries/drug effects , Female , Heart Rate/drug effects , Heart Rate/physiology , Humans , Hypertension/physiopathology , Male , Middle Aged , Pulse Wave AnalysisABSTRACT
OBJECTIVES: To explore synergistic effect between angiotensin II receptor blockers (ARBs) and statins on Th17/Treg functional imbalance in hypertensive patients with carotid atherosclerosis. METHODS: This study was a 2 × 2 factorial randomized, prospective, double-blind, placebo-controlled trial. One hundred and fifty nine hypertensive patients with carotid atherosclerosis were randomized to the administration of control group, telmisartan group, rosuvastatin group, and combination group (telmisartan plus rosuvastatin) base on hydrochlorothiazide treatment. Carotid ultrasonography, parameters of Th17/Treg functional axis, interleukin (IL)-1ß, IL-2, interferon (IFN)-γ, hypersensitive C-reactive protein (hsCRP), monocyte chemotactic protein (MCP)-1 were evaluated. RESULTS: Blood pressure level markedly reduced in four groups. There was significantly synergistic effect of combination of telmisartan with rosuvastatin on reducing carotid imtima-media thickness (IMT), Th17 cells frequency, IL-17, IL-6, IL-23, tumor necrosis factor (TNF)-α, expression of retinoic acid receptor-related orphan receptor (ROR)γt mRNA, Th17/Treg ratio, IL-1ß, IL-2, IFN-γ, hsCRP, and MCP-1, and increasing Treg cells frequency, IL-10, transforming growth factor(TGF)-ß1, and expression of forkhead/winged helix transcription factor (Foxp3) mRNA (all P<0.05). Change rate of IMT statistical positively related to descent rates of Th17 cells frequency, IL-17, IL-6, IL-23, TNF-α, expression of RORγt mRNA, Th17/Treg ratio, IL-1ß, IL-2, IFN-γ, hsCRP, and MCP-1, and negatively related to increased rates of Treg frequency, IL-10, TGF-ß1, and expression of Foxp3 mRNA, respectively (all P<0.05). CONCLUSION: There is a synergistic effect of combination of telmisartan with rosuvastatin on ameliorating Th17/Treg functional imbalance in hypertensive patients with carotid atherosclerosis.
