G6PD maintains the VSMC synthetic phenotype and accelerates vascular neointimal hyperplasia by inhibiting the VDAC1-Bax-mediated mitochondrial apoptosis pathway.

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) plays an important role in vascular smooth muscle cell (VSMC) phenotypic switching, which is an early pathogenic event in various vascular remodeling diseases (VRDs). However, the underlying mechanism is not fully understood. METHODS: An IP‒LC‒MS/MS assay was conducted to identify new binding partners of G6PD involved in the regulation of VSMC phenotypic switching under platelet-derived growth factor-BB (PDGF-BB) stimulation. Co-IP, GST pull-down, and immunofluorescence colocalization were employed to clarify the interaction between G6PD and voltage-dependent anion-selective channel protein 1 (VDAC1). The molecular mechanisms involved were elucidated by examining the interaction between VDAC1 and apoptosis-related biomarkers, as well as the oligomerization state of VDAC1. RESULTS: The G6PD level was significantly elevated and positively correlated with the synthetic characteristics of VSMCs induced by PDGF-BB. We identified VDAC1 as a novel G6PD-interacting molecule essential for apoptosis. Specifically, the G6PD-NTD region was found to predominantly contribute to this interaction. G6PD promotes VSMC survival and accelerates vascular neointimal hyperplasia by inhibiting VSMC apoptosis. Mechanistically, G6PD interacts with VDAC1 upon stimulation with PDGF-BB. By competing with Bax for VDAC1 binding, G6PD reduces VDAC1 oligomerization and counteracts VDAC1-Bax-mediated apoptosis, thereby accelerating neointimal hyperplasia. CONCLUSION: Our study showed that the G6PD-VDAC1-Bax axis is a vital switch in VSMC apoptosis and is essential for VSMC phenotypic switching and neointimal hyperplasia, providing mechanistic insight into early VRDs.

Hsa_circ_0001402 alleviates vascular neointimal hyperplasia through a miR-183-5p-dependent regulation of vascular smooth muscle cell proliferation, migration, and autophagy.

INTRODUCTION: Vascular neointimal hyperplasia, a pathological process observed in cardiovascular diseases such as atherosclerosis and pulmonary hypertension, involves the abundant presence of vascular smooth muscle cells (VSMCs). The proliferation, migration, and autophagy of VSMCs are associated with the development of neointimal lesions. Circular RNAs (circRNAs) play critical roles in regulating VSMC proliferation and migration, thereby participating in neointimal hyperplasia. However, the regulatory roles of circRNAs in VSMC autophagy remain unclear. OBJECTIVES: We aimed to identify circRNAs that are involved in VSMC autophagy-mediated neointimal hyperplasia, as well as elucidate the underlying mechanisms. METHODS: Dual-luciferase reporter gene assay was performed to validate two competing endogenous RNA axes, hsa_circ_0001402/miR-183-5p/FKBP prolyl isomerase like (FKBPL) and hsa_circ_0001402/miR-183-5p/beclin 1 (BECN1). Cell proliferation and migration analyses were employed to investigate the effects of hsa_circ_0001402, miR-183-5p, or FKBPL on VSMC proliferation and migration. Cell autophagy analysis was conducted to reveal the role of hsa_circ_0001402 or miR-183-5p on VSMC autophagy. The role of hsa_circ_0001402 or miR-183-5p on neointimal hyperplasia was evaluated using a mouse model of common carotid artery ligation. RESULTS: Hsa_circ_0001402 acted as a sponge for miR-183-5p, leading to the suppression of miR-183-5p expression. Through direct interaction with the coding sequence (CDS) of FKBPL, miR-183-5p promoted VSMC proliferation and migration by decreasing FKBPL levels. Besides, miR-183-5p reduced BECN1 levels by targeting the 3'-untranslated region (UTR) of BECN1, thus inhibiting VSMC autophagy. By acting as a miR-183-5p sponge, overexpression of hsa_circ_0001402 increased FKBPL levels to inhibit VSMC proliferation and migration, while simultaneously elevating BECN1 levels to activate VSMC autophagy, thereby alleviating neointimal hyperplasia. CONCLUSION: Hsa_circ_0001402, acting as a miR-183-5p sponge, increases FKBPL levels to inhibit VSMC proliferation and migration, while enhancing BECN1 levels to activate VSMC autophagy, thus alleviating neointimal hyperplasia. The hsa_circ_0001402/miR-183-5p/FKBPL axis and hsa_circ_0001402/miR-183-5p/BECN1 axis may offer potential therapeutic targets for neointimal hyperplasia.

Integrated analysis of tRNA-derived small RNAs in proliferative human aortic smooth muscle cells.

BACKGROUND: Abnormal proliferation of vascular smooth muscle cells (VSMCs) contributes to vascular remodeling diseases. Recently, it has been discovered that tRNA-derived small RNAs (tsRNAs), a new type of noncoding RNAs, are related to the proliferation and migration of VSMCs. tsRNAs regulate target gene expression through miRNA-like functions. This study aims to explore the potential of tsRNAs in human aortic smooth muscle cell (HASMC) proliferation. METHODS: High-throughput sequencing was performed to analyze the tsRNA expression profile of proliferative and quiescent HASMCs. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to validate the sequence results and subcellular distribution of AS-tDR-001370, AS-tDR-000067, AS-tDR-009512, and AS-tDR-000076. Based on the microRNA-like functions of tsRNAs, we predicted target promoters and mRNAs and constructed tsRNA-promoter and tsRNA-mRNA interaction networks. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to reveal the function of target genes. EdU incorporation assay, Western blot, and dual-luciferase reporter gene assay were utilized to detect the effects of tsRNAs on HASMC proliferation. RESULTS: Compared with quiescent HASMCs, there were 1838 differentially expressed tsRNAs in proliferative HASMCs, including 887 with increased expression (fold change > 2, p < 0.05) and 951 with decreased expression (fold change < ½, p < 0.05). AS-tDR-001370, AS-tDR-000067, AS-tDR-009512, and AS-tDR-000076 were increased in proliferative HASMCs and were mainly located in the nucleus. Bioinformatics analysis suggested that the four tsRNAs involved a variety of GO terms and pathways related to VSMC proliferation. AS-tDR-000067 promoted HASMC proliferation by suppressing p53 transcription in a promoter-targeted manner. AS-tDR-000076 accelerated HASMC proliferation by attenuating mitofusin 2 (MFN2) levels in a 3'-untranslated region (UTR)-targeted manner. CONCLUSIONS: During HASMC proliferation, the expression levels of many tsRNAs are altered. AS-tDR-000067 and AS-tDR-000076 act as new factors promoting VSMC proliferation.

Pipeline Embolization Device for Salvage Treatment of a Willis Covered Stent Prolapse Into the Aneurysmal Sac.

The Willis covered stent (WCS) may prolapse into the aneurysmal sac due to device migration or foreshortening. We present a useful salvage strategy that can reorient a prolapsed WCS into a more suitable alignment. An intra-procedural prolapse of a WCS into a large cavernous aneurysm occurred in a 70-year-old female patient. A pipeline embolization device (PED) was used to retrieve the WCS and successfully accomplish flow diversion. Maintaining proximal access and ensuring that the microwire is securely held within the central axis of the herniated stent are critical until the entire parent vessel can be reconstructed. This salvage technique may help to regain proximal access and reposition the flow diversion constructs following WCS prolapse.

Endovascular Treatment of the Huge Dissecting Aneurysms Involving the Basilar Artery by the Internal Trapping Technique: Technical Note.

BACKGROUND: The endovascular strategy of the huge dissecting aneurysms involving the basilar artery (BA) is controversial and challenging. This study was to investigate the clinical and angiographic outcomes of the treatment of the huge dissecting aneurysms involving the BA by the internal trapping (IT) technique. METHODS: We retrospectively studied 15 patients with the huge dissecting aneurysms involving the BA treated by the IT technique between September 2005 and September 2014 in Department of Interventional Neuroradiology of Beijing Tiantan Hospital. Clinical and angiographic data were reviewed and evaluated. RESULTS: All patients were treated by the IT technique. That meant the dissecting artery and aneurysm segments were completed occlusion. After the procedure, the angiography demonstrated that all the dissecting artery and aneurysm segments were completed occlusion. Follow-up angiography was performed at 3-6 months or 12-18 months after the endovascular treatment (median 8 months), 14 patients had a good recovery. Re-canalization occurred in one patient whose aneurysm involved in bilateral vertebral arteries and the two third of the middle-lower BA. After the second treatment, the patient died by the ventricular tachycardia. CONCLUSIONS: The IT technique is a technically feasible and safe alternative for the treatment of BA dissecting aneurysms, but it is not necessarily the safest or most definitive treatment modality. The ideal treatment of the huge dissecting aneurysms involving the BA remains debatable and must be investigated on a case-by-case basis.

Polymorphisms in DNA repair genes and risk of glioma and meningioma.

Polymorphisms in DNA repair genes have been shown to influence DNA repair processes and to modify cancer susceptibility. Here we conducted a case-control study to assess the role of potential SNPs of DNA repair genes on the risk of glioma and meningioma. We included 297 cases and 458 cancer-free controls. Genotyping of XRCC1 Gln399Arg, XRCC1 Arg194Trp, XRCC2 Arg188His, XRCC3 Thr241Met, XRCC4 Ala247Ser, ERCC1 Asn118Asp, ERCC2 Lys751Gln and ERCC5 Asp1558His were performed in a 384-well plate format on the Sequenom MassARRAY platform. XRCC1 Arg194Trp (rs1799782) and ERCC2 Asp312Asn rs1799793 did not follow the HWE in control group, and genotype distributions of XRCC1 Gln399Arg rs25487, XRCC2 Arg188His rs3218536 and ERCC2 Asp312Asn rs1799793 were significantly different between cases and controls (P<0.05). We found XRCC1 399G/G, XRCC1 194 T/T and XRCC3 241T/T were associated with a higher risk when compared with the wild-type genotype. For ERCC5 Asp1558His, we found G/G genotype was associated with elevated susceptibility. In conclusion, our study has shown that XRCC1 Gln399Arg, XRCC1 Arg194Trp, XRCC3 Thr241Met and ERCC5 Asp1558His are associated with risk of gliomas and meningiomas. This finding could be useful in identifying the susceptibility genes for these cancers.

Embolization of brain arteriovenous malformations with ethylene vinyl alcohol copolymer: technical aspects.

BACKGROUND: Endovascular therapy plays an important role in the treatment of brain arteriovenous malformations (BAVMs). Ethylene vinyl alcohol copolymer (Onyx) is a novel liquid embolic material. This study aimed to summarize our experience of using Onyx for embolization of BAVMs with the focus on embolization technique. METHODS: From September 2003 to November 2007, 115 patients (43 women and 72 men, with a mean age of 29 years) with BAVMs were endovascularly treated with Onyx in our department. The following features of all AVMs were evaluated prior to treatment: type of nidus and shunt, draining veins, and feeding arteries. A total of 196 endovascular procedures were performed. RESULTS: The course of endovascular treatment was completed in 88 patients. Additional sessions were planned in 27 patients. Of the 88 patients, total occlusion was obtained in 23 patients (26.1%), near-total (> 80% of the original volume) occlusion was obtained in 35 patients (39.8%) and partial occlusion (< 80% of the original volume) was obtained in 30 patients (34.1%) using embolization as the sole therapeutic technique. Mean volume reduction was 72% (range 30% - 100%) in 115 patients. Thirty four patients (38.6%, 34/88) underwent radiosurgical treatment. Additional embolization sessions were planned in 27 patients. Complications occurred in 19 patients (16.5%, 19/115), leading to death in one patient (mortality 0.9%) and permanent disabling in 3 patients (morbidity 2.6%). CONCLUSIONS: Onyx was shown to be feasible and safe for embolization of BAVMs. Proper use of the Onyx injection technique largely improved the endovascular treatment of BAVMs. Large AVMs can be adequately reduced in size through the use of additional treatment.

[Three-dimensional numerical simulation and hemodynamic analysis of intracranial longitypical aneurysms].

OBJECTIVE: To establish a model of three-dimensional numerical simulation of intracranial longitypical aneurism and analyze the hemodynamic features thereof. METHODS: Ten patients with intracranial longitypical aneurism underwent surgical treatment. Intracranial vascular ultrasonography was conducted before operation. Intra-operatively three-dimensional angiography of the aneurysm was conducted and multifunctional physiological monitor was used to record the dynamic pressure and pressure wave form of the main branch parent artery. Matlab, Ansys, and Fluent software were used to simulate the blood flow of the longitypical aneurysms. RESULTS: The hemodynamic parameter levels were the highest at the inflow tract, followed by those at the outflow tract, and were the lowest at the top of aneurysm, for example, the blood flow velocity was (1.07+/-0.23) m/s, the dynamic pressure was (574+/-186) Pa, and the wall shear stress was (7.7+/-2.0) Pa at the inflow tract, all significantly higher than those at the top [(0.15+/-0.07) m/s, (37+/-13) Pa, and (0.40+/-0.13) Pa respectively, all P<0.05]. No eddy or just simple eddy occurred in the aneurysm. CONCLUSION: The dynamic pressure, velocity, and wall shear stress are the lowest at the top of longitypical aneurysm which may contribute to the rupture of aneurysm.

Endovascular treatment of wide-necked intracranial aneurysms using of "remodeling technique" with the HyperForm balloon.

BACKGROUND: Aneurysms with wide-necked or a large neck/fundus ratio, especially located on an arterial bifurcation or a small artery, are challenges for interventional neuroradiologist because of the risk of coil migration or coil protrusion into the parent vessels. Our study was designed to improve the efficacy and safety of the "remodeling technique" with the HyperForm balloon for these difficult aneurysms and was confirmed by a follow-up result. METHODS: From June 2004 to September 2006, forty-two patients (20 men, 22 women) with wide-necked or large neck/fundus ratio aneurysms were treated by using the "remodeling technique" with the HyperForm balloon. RESULTS: Forty wide-necked aneurysms were successfully treated with the HyperForm balloon remodeling technique with only two failed cases. Final results consisted of total occlusion in 34 cases (80.9%), subtotal in 4 (9.5%) and incomplete in 2 (4.8%). One aneurysmal rupture occurred, but no clinical consequence was shown. No thromboembolic events were observed during treatment. Final angiographic follow-up time ranged from 3 to 18 months. CONCLUSIONS: The "remodeling technique" with the HyperForm balloon is a very useful tool in the treatment of wide-necked or unfavorable neck/fundus ratio intracranial aneurysms-located on an arterial bifurcation or a small artery and, especially, located on the bifurcation of a large artery and a small one. In our experience, this technique provided a safe and efficient treatment for difficult aneurysms when the standard remodeling technique might have failed.