Recombinant Human Hepatocyte Growth Factor Plasmids for Treating Patients with Chronic Limb Threatening Ischaemia: A Systematic Review and Meta-analysis.

OBJECTIVE: Recombinant human hepatocyte growth factor (HGF) plasmids are novel alternatives to salvage limbs in patients with chronic limb threatening ischaemia (CLTI). A systematic review and meta-analysis of data was conducted to assess the therapeutic efficacy of HGF plasmids in patients with CLTI. DATA SOURCES: Randomised controlled studies evaluating HGF plasmid efficacy in patients with CLTI were identified using MEDLINE, Embase, Cochrane Database of Systematic Reviews, and ClinicalTrials.gov databases. REVIEW METHODS: Meta-analyses of the reported relative risk (RR) or mean difference (MD) were conducted. Subgroup analyses were performed to determine the efficacy of HGF plasmids in cohorts excluding Buerger's disease. Certainty of evidence for each outcome was assessed. RESULTS: Seven studies (n = 655 participants) were included. Based on low certainty evidence, patients treated with HGF had a significantly higher complete ulcer healing rate (RR 1.99, 95% confidence interval [CI] 1.30 - 3.04; p = .002) than patients treated with placebo. HGF treatment was associated with reduced visual analogue scale (VAS) scores of pain severity (MD -1.56, 95% CI -2.12 - -1.00; p < .001) vs. placebo in patients with CLTI assessed at three month follow up (low certainty evidence); no significant differences were observed in major amputation (RR 0.91, 95% CI 0.48 - 1.73; p = .77) (low certainty evidence) or all cause mortality rate (RR 0.93, 95% CI 0.38 - 2.27; p = .87) (low certainty evidence) between patients treated with HGF and placebo. Low certainty evidence suggested no significant differences in change in ankle brachial index at six months (MD 0.00, 95% CI -0.09 - 0.09; p = 1.0) between patients treated with HGF and placebo. The complete ulcer healing rate and improved three month VAS scores of pain severity benefits persisted in subgroup analyses (low certainty evidence). CONCLUSION: Low certainty evidence suggested that HGF treatment is associated with an increased complete ulcer healing rate and reduced ischaemic pain in patients with CLTI.

Ant-Neointimal Formation Effects of SLC6A6 in Preventing Vascular Smooth Muscle Cell Proliferation and Migration via Wnt/ß-Catenin Signaling.

Vascular smooth muscle cells (VSMCs) play an important role in the pathogenesis of vascular remolding, such as atherosclerosis and restenosis. Solute carrier family 6 member 6 (SLC6A6) is a transmembrane transporter that maintains a variety of physiological functions and is highly expressed in VSMCs. However, its role on VSMCs during neointimal formation remains unknown. In this study, mRNA and protein levels of SLC6A6 were examined using models of VSMC phenotype switching in vivo and in vitro and human artery samples with or without atherosclerosis. SLC6A6 gain- and loss-of-function approaches were performed by adenovirus infection or small interfering RNA (siRNA) transfection, respectively. Reactive oxygen species (ROS), proliferation, migration, and phenotype-related proteins of VSMCs were measured. Vascular stenosis rate and related genes were assessed in a rat vascular balloon injury model overexpressing SLC6A6. SLC6A6 was downregulated in dedifferentiated VSMCs, atherosclerotic vascular tissues, and injured vascular tissues. SLC6A6 suppressed VSMC proliferation and migration, while increasing contractile VSMC proteins. Mechanistically, SLC6A6 overexpression reduced ROS production and inhibited the Wnt/ß-catenin pathway. Furthermore, SLC6A6 overexpression suppressed neointimal formation in vivo. Collectively, overexpression of SLC6A6 suppresses neointimal formation by inhibiting VSMC proliferation and migration via Wnt/ß-catenin signaling and maintaining the VSMC contractile phenotype.

Myeloid-derived MIF drives RIPK1-mediated cerebromicrovascular endothelial cell death to exacerbate ischemic brain injury.

Macrophage migration inhibitory factor (MIF) is a multifaced protein that plays important roles in multiple inflammatory conditions. However, the role of MIF in endothelial cell (EC) death under inflammatory condition remains largely unknown. Here we show that MIF actively promotes receptor-interacting protein kinase 1 (RIPK1)-mediated cell death under oxygen-glucose deprivation condition. MIF expression is induced by surgical trauma in peripheral myeloid cells both in perioperative humans and mice. We demonstrate that MIF-loaded myeloid cells induced by peripheral surgery adhere to the brain ECs after distal middle cerebral artery occlusion (dMCAO) and exacerbate the blood-brain barrier (BBB) disruption. Genetic depletion of myeloid-derived MIF in perioperative ischemic stroke (PIS) mice with MCAO following a surgical insult leads to significant reduction in ECs apoptosis and necroptosis and the associated BBB disruption. The adoptive transfer of peripheral blood mononuclear cells (PBMC) from surgical MIFΔLyz2 mice to wild-type (WT) MCAO mice also shows reduced ECs apoptosis and necroptosis compared to the transfer of PBMC from surgical MIFf  l/f  l mice to MCAO recipients. The genetic inhibition of RIPK1 also attenuates BBB disruption and ECs death compared to that of WT mice in PIS. The administration of MIF inhibitor (ISO-1) and RIPK1 inhibitor (Nec-1s) can both reduce the brain EC death and neurological deficits following PIS. We conclude that myeloid-derived MIF promotes ECs apoptosis and necroptosis through RIPK1 kinase-dependent pathway. The above findings may provide insights into the mechanism as how peripheral inflammation promotes the pathology in central nervous system.

Neuronal Serpina3n is an endogenous protector against blood brain barrier damage following cerebral ischemic stroke.

Ischemic stroke results in blood-brain barrier (BBB) disruption, during which the reciprocal interaction between ischemic neurons and components of the BBB appears to play a critical role. However, the underlying mechanisms for BBB protection remain largely unknown. In this study, we found that Serpina3n, a serine protease inhibitor, was significantly upregulated in the ischemic brain, predominantly in ischemic neurons from 6 hours to 3 days after stroke. Using neuron-specific adeno-associated virus (AAV), intranasal delivery of recombinant protein, and immune-deficient Rag1-/- mice, we demonstrated that Serpina3n attenuated BBB disruption and immune cell infiltration following stroke by inhibiting the activity of granzyme B (GZMB) and neutrophil elastase (NE) secreted by T cells and neutrophils. Furthermore, we found that intranasal delivery of rSerpina3n significantly attenuated the neurologic deficits after stroke. In conclusion, Serpina3n is a novel ischemic neuron-derived proteinase inhibitor that counterbalances BBB disruption induced by peripheral T cell and neutrophil infiltration after ischemic stroke. These findings reveal a novel endogenous protective mechanism against BBB damage with Serpina3n being a potential therapeutic target in ischemic stroke.

Clinical Outcomes of Distal Tapered Restrictive Covered Stent Applied in Endovascular Treatment of Aortic Dissection Involving Zone 0.

OBJECTIVE: The safety and efficacy of a distal tapered restrictive covered stent (RCS) applied in the endovascular treatment of aortic dissection involving Zone 0 was evaluated. METHODS: This study retrospectively analysed 43 patients with acute aortic dissection involving Zone 0 who received in situ laser fenestrated thoracic endovascular aortic repair with distal tapered RCS from January 2015 to February 2019. The indication for the distal tapered RCS procedure was an inappropriate distal size of the main stent graft. Technical success, aortic remodelling, and clinical outcomes were evaluated. RESULTS: Technical success was achieved in all patients. The 30 day post-operative mortality rate was 0%. All patients had complete false lumen thrombosis in the stent coverage segment. True lumen volume increased significantly (p < .001) with an average change of 87.0% ± 34.3%, while false lumen volume decreased significantly (p < .001) with an average change of -71.0% ± 13.5% between baseline and 12 months. During the follow up period (mean 28.7 months, range 12-63 months), no distal stent graft induced new entry (SINE) was observed. The average distance between the distal end of the RCS and the coeliac trunk was 57.5 mm. Two (4.7%) patients had spinal cord ischaemia (SCI) and recovered without permanent paraplegia after undergoing conservative treatment. CONCLUSION: The distal tapered RCS applied in the endovascular treatment of aortic dissection involving Zone 0 is considered to be a feasible and effective approach along with satisfactory aortic remodelling, a low risk of SINE, and SCI. The favourable results are partly explained by selection. No patients had an entry tear near the coronary artery, nor were the coronary arteries, pericardium, or aortic valve involved at the time of repair.