ALAS2 overexpression alleviates oxidative stress-induced ferroptosis in aortic aneurysms via GATA1 activation.

Background: Aortic aneurysm, characterized by abnormal dilation of the aorta, poses significant health risks. This study aims to investigate the interaction between 5-aminolevulinate synthase 2 (ALAS2) and GATA-binding protein 1 (GATA1) in ferroptosis and oxidative stress responses in aortic aneurysm. Methods: A weighted gene co-expression network analysis (WGCNA) was performed on the differentially expressed genes (DEGs) within the GSE9106 dataset to identify the key module. Subsequently, protein-protein interaction (PPI) network analysis was performed on the key module. Mouse aortic vascular smooth muscle cells (MOVAS) were treated with hydrogen peroxide (H2O2) to induce oxidative stress, and ferroptosis inducers and inhibitors were added to evaluate their effects on iron content and oxidative stress markers. Through a series of in vitro cellular experiments, we assessed cell viability, expression levels of GATA1 and iron mutation-associated proteins, as well as cellular phenotypes such as inflammatory responses and apoptosis rates. Results: Three candidate genes (ALAS2, GYPA, and GYPB) were upregulated in the thoracic aortic aneurysm (TAA) samples of the GSE9106 dataset. The H2O2 treatment increased the MOVAS cells' iron content and oxidative stress, upregulated ALAS2 protein levels, and decreased the ferroptosis-related protein levels. ALAS2 overexpression reversed H2O2-induced apoptosis and increased the inflammatory cytokine levels. Additionally, the knockdown of GATA1 partially reversed the protective mechanism of overexpressed ALAS2 on H2O2-induced ferroptosis. Conclusions: ALAS2 overexpression reduced H2O2-induced oxidative damage and iron-induced apoptosis in MOVAS cells, and GATA1 knockdown partially reversed this protective effect. These findings suggested that the ALAS2 and GATA1 regulatory pathways may be potential therapeutic targets in aortic aneurysms.

Endovascular Treatment of Superior Mesenteric Artery Pseudoaneurysm Due to Infective Endocarditis With Stent-Graft.

PURPOSE: To report a successful case of pseudoaneurysm of the superior mesenteric artery (SMA) caused by infected endocarditis treated with a covered stent. CASE REPORT: A patient was diagnosed with infective endocarditis and 2 months later a proximal SMA pseudoaneurysm was identified on computed tomography. Daptomycin was started on admission and continued for approximately 4 months until the inflammatory markers normalized, and then the SMA pseudoaneurysm was successfully excluded with a stent-graft and antibiotics were continued for 1 year after the procedure. There were no associated complications or recurrences at the 3-year follow-up. CONCLUSION: Placing a covered stent with a full course of antibiotics before and after surgery may be a successful alternative to open surgery in the treatment of pseudoaneurysms of the SMA due to infective endocarditis. CLINICAL IMPACT: This case report reports a rare case of pseudoaneurysm of the superior mesenteric artery due to infective endocarditis, which was successfully treated with an overlapping stent and confirmed by complete imaging data at a three-year follow-up. This report suggests that endovascular treatment may be an alternative to open surgery in the treatment of pseudoaneurysms of the superior mesenteric artery caused by infective endocarditis.

Acute Renal Infarction Due to Symptomatic Isolated Spontaneous Renal Artery Dissection: A Rare and Fatal Disease.

OBJECTIVE: To report demographics and clinical, laboratory, and imaging features of acute renal infarction (ARI) due to symptomatic isolated spontaneous renal artery dissection (SISRAD) and to analyze outcomes after the initial therapy for SISRAD. METHODS: Thirteen patients with ARI due to SISRAD between January 2016 and March 2021 were enrolled in this retrospective study. We reviewed the demographics, clinical, laboratory, and imaging features (location of the infarct kidney, the branch artery involved by dissection, true lumen stenosis, false lumen thrombosis, and aneurysm), treatment modalities, and follow-up results; analyzed the difference between SISRAD and other causes of ARI; and propose an appropriate therapy strategy for SISRAD based on our data and literature. RESULT: Patients with ARI due to SISRAD were mostly young men (43 [24-53] years; 12/13 [92%]). No patients had atrial fibrillation or acute kidney injury at admission (0/13). All 13 patients received conservative treatment as the initial treatment. Sixty-two percent (8/13) of patients progressed, and 88% (7/8) of them had dissection aneurysm on the admission computed tomographic angiography (CTA) image. Seventy-five percent (6/8) of patients underwent endovascular intervention as follows, stent placement in 1 patient, renal artery embolization in 1, and stent placement with embolization in 4. Two patients with disease progression died: 1 during the conservative treatment period and 1 after the stent placement. Thirty-eight percent (5/13) of patients in remission continued to receive conservative treatment, none of whom had dissection aneurysm on the admission CTA. CONCLUSION: Symptomatic isolated spontaneous renal artery dissection is a rare and fatal disease. For young ARI patients with no previous history of tumors and cardiogenic diseases, CTA examination is recommended to exclude SISRAD. Dissection aneurysm seems to be a risk of progression for SISRAD in this series. Conservative treatment, a recognized initial treatment, has a good effect on patients without dissection aneurysm, and we recommend endovascular intervention as the initial treatment for the patient with dissection aneurysm at admission. Multicenter clinical studies are needed to explore a more-appropriate treatment for patients with SISRAD. CLINICAL IMPACT: This article report the related factors, risks, demographics and laboratory data of Acute renal infarction (ARI) due to Symptomatic isolated spontaneous renal artery dissection (SISRAD) and explore a better initial therapy strategy for SISRAD. It will help improve the effectiveness of SISRAD treatment and reduce the mortality rate from this rare but lethal disease.

Experimental Analysis of In Situ Fenestration of Endovascular Stent-Grafts: Comparison between Needle and Laser Puncture.

BACKGROUND: To evaluate the quality of in vitro fenestrations during in situ fenestration (ISF) and investigate the differences between needle and laser puncture in current stent-grafts. METHODS: An in vitro study evaluated the damage created by needle ISF on stent-graft fabrics versus laser ISF. Fenestrations were made in 5 different commercially available stent-grafts, including polyester stent-grafts (Relay, Valiant and Hercules) and expanded polytetrafluoroethylene (ePTFE) stent-grafts (TAG and Ankura). Each stent-graft received fenestration by needle and laser separately, followed by gradual dilation (4 mm, 6 mm, 8 mm, and 10 mm sequentially) of noncompliant balloons. Quantitative and qualitative evaluations including fenestration diameter, area, shape and margins were conducted using light microscopy and scanning electron microscope. RESULTS: The primary fenestrations created by needle were slit-like with visible cut-off fibers in polyester stent-grafts and were almost circular with clear margins in ePTFE stent-grafts; those created by laser were squared or elliptical with ragged edges and burned fibers in all the stent-grafts. Fabric debris and toxic particles due to burning of the material were generated during laser-assisted fenestration. The Primary holes in polyester stent-grafts (Relay, Valiant and Hercules) by needle showed smaller area (0.05 mm2 vs. 0.22 mm2, 0.52 mm2 vs. 0.70 mm2 and 0.28 mm2 vs. 0.46 mm2; P < 0.01) and worse shape (0.93 vs. 2.46, 1.17 vs. 2.33 and 0.93 vs. 2.47; P < 0.01) than those by laser, while larger area (0.67 vs.0.43, 0.59 vs.0.45; P < 0.05), better shape (3.93 vs. 2.53, 3.90 vs. 2.93; P < 0.05) and better margin (3.83 vs. 2.47, 3.83 vs. 2.53; P < 0.05) in ePTFE stent-grafts (TAG and Ankrura). After gradual balloon dilation, the final holes showed no evident difference in maximal length, fenestration area, scores of shape and margin between the 2 ways of fenestration (P > 0.05). Ankura stent-graft showed the largest holes with best quality than the others. CONCLUSIONS: The primary fenestrations were different between needle and laser puncture, laser induced fabric debris and toxic particles release should be cautiously considered. The final fenestrations were similar after gradual balloon dilation.

Nuclear Factor Kappa-B/Homeobox A9-Mediated Modulation of Leucine-Rich Repeat Flightless-Interacting Protein 1 Is Involved in Advanced Glycation End Product-Induced Endothelial Dysfunction.

BACKGROUND: Pathogenesis of cardiovascular diseases begins with endothelial dysfunction. Our previous study has shown that advanced glycation end products (AGE) could inhibit the expression of homeobox A9 (Hoxa9), thereby inducing endothelial dysfunction. Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1) has been found to participate in a variety of pathological processes, but reports of its role in endothelial dysfunction are rare. OBJECTIVES: This study aims to investigate whether LRRFIP1 is involved in AGE-induced endothelial dysfunction through Hoxa9-mediated transcriptional activation. METHODS: Chromatin immunoprecipitation was used to detect the transcriptional regulation of Hoxa9 on LRRFIP1 promoters. Human umbilical vein endothelial cells were treated with AGE or pyrrolidinedithiocarbamate (nuclear factor kappa-B [NF-κB] inhibitor). Moreover, changes in apoptosis, proliferation, migration, release of nitric oxide, and angiogenesis were detected. RESULTS: Hoxa9 promotes LRRFIP1 expression by binding to the -LRRFIP1 promoter. Meanwhile, overexpression of LRRFIP1 inhibited phosphorylation of P65 and elevated expression of Hoxa9. Overexpression of LRRFIP1 or/and Hoxa9 reversed the effects of AGE on HUVEC. AGE-induced inhibition on the expression of LRRFIP1 and Hoxa9 could be reversed by the NF-κB inhibitor. CONCLUSION: LRRFIP1 is involved in AGE-induced endothelial dysfunction via being regulated by the NF-κB/Hoxa9 axis.

Long-term Results of Thoracic Endovascular Aortic Repair for Type B Aortic Dissection and Risk Factors for Survival.

Purpose: To compare characteristics of acute, subacute, and chronic type B aortic dissection and their influence on long-term results of thoracic endovascular aortic repair (TEVAR). Materials and Methods: In a single-center, retrospective cohort study, 314 patients (median age 52 years; 244 men) with acute (n=165), subacute (n=115), or chronic (n=34) type B aortic dissection underwent TEVAR between January 2009 and December 2013. Patient demographics, risk factors, and imaging characteristics were compared among the groups. Univariable and multivariable Cox regression analyses were performed to identify any factors influencing survival. Results: The acute and subacute patients exhibited more complications at presentation than chronic patients. However, the chronic patients exhibited more aneurysmal dilatation (p<0.001) and true lumen collapse (p<0.001). Over a mean follow-up of 68.1±22.9 months (range 2-108), subacute patients showed a lower reintervention rate (3.6% vs 12.1% vs 12.1%, p=0.045), a lower major complication rate (14.4% vs 33.1% vs 27.3%, p=0.002), and better cumulative overall survival (p=0.03) than the acute and chronic groups, respectively. Furthermore, acute patients developed more stent-graft-induced distal erosion (p=0.017) and retrograde type A dissection (RTAD) (p=0.036), whereas chronic patients had less aortic remodeling in the stented segment (p<0.001), distal thoracic aorta (p<0.001), and abdominal aorta (p=0.047). Finally, multivariable analysis demonstrated age >52 years, visceral malperfusion, and RTAD as independent factors influencing overall survival; aneurysmal dilatation, rupture/impending rupture, and RTAD were independent factors influencing aorta-specific survival. Conclusion: Acute and subacute patients had increased risks of rupture and complications at presentation, whereas chronic patients had increased risks for aneurysmal dilatation. From a long-term perspective, the subacute phase might be an optimal time for TEVAR in cases of type B aortic dissection that do not need emergent interventions. The risk factors influencing survival should be identified, carefully managed, and possibly prevented.

Long non-coding RNA GAPLINC promotes angiogenesis by regulating miR-211 under hypoxia in human umbilical vein endothelial cells.

In this study, we investigated the role of a long non-coding RNA GAPLINC in angiogenesis using human umbilical vein endothelial cells (HUVEC). We found that hypoxia and hypoxia-inducible factor 1α (HIF-1α) increased the expression of GAPLINC in HUVEC cells. Moreover, GAPLINC overexpression down-regulated miR-211 and up-regulated Bcl2 protein expression. Further rescue experiments confirmed that hypoxia directly increased GAPLINC expression. GAPLINC overexpression also increased cell migration and vessel formation which promoted angiogenesis, and these changes were attributed to the increased expression of vascular endothelial growth factor receptors (VEGFR) and delta-like canonical notch ligand 4 (DLL4) receptors. Finally, we demonstrated that GAPLINC promotes vessel formation and migration by regulating MAPK and NF-kB signalling pathways. Taken together, these findings comprehensively demonstrate that overexpression of GAPLINC increases HUVEC cells angiogenesis under hypoxia condition suggesting that GAPLINC can be a potential target for critical limb ischaemia (CLI) treatment.

Humanin prevents high glucose-induced monocyte adhesion to endothelial cells by targeting KLF2.

Endothelial dysfunction and vascular complications induced by hyperglycemia play an important role in the pathological development of atherosclerosis in diabetes. Humanin, a 24-amino acid mitochondria-derived polypeptide, has displayed its cytoprotective effects in diverse cell types and tissues. In the current study, we aimed to characterize the effects of humanin on high glucose-induced endothelial dysfunction. Firstly, we found that humanin treatment induced the expression of Krüppel-like factor 2 (KLF2), an essential transcriptional regulator of endothelial function, at the transcriptional level in human umbilical vein endothelial cells (HUVECs). Additionally, our results indicate that humanin treatment regulated the expression of KLF2 target genes such as endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1). Evidence demonstrated that the effects of humanin on KLF2 expression was mediated by the phosphorylation of extracellular signal regulated kinase 5 (ERK5). Furthermore, humanin restored high glucose-induced reduction of KLF2 expression. We also showed that humanin significantly reduced the expression of vascular cell adhesion molecule 1 (VCAM-1) and E-selectin. Notably, humanin treatment markedly prevented high glucose-induced attachment of the monocyte THP-1 cells to HUVECs. However, knockdown of KLF2 abolished these effects. Lastly, we report that humanin treatment inhibited high glucose-induced secretion of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß). These findings suggest that humanin may have therapeutic potential for the treatment of hyperglycemia-associated endothelial dysfunction.

Long Noncoding RNA AK12348 is Involved in the Regulation of Myocardial Ischaemia-Reperfusion Injury by Targeting PARP and Caspase-3.

BACKGROUD: Recently long non-coding RNAs (lncRNAs) have attracted attention in several biomedical fields. The purpose of this study is to investigate the profile of myocardial lncRNAs and their potential roles in myocardial ischaemia-reperfusion injury (IRI). METHODS: EdgeR bioconductor package was used to screen differentially expressed lncRNAs in myocardial IRI, and lncRNA AK12348 was selected. The mRNA levels of lncRNA AK12348 in normal and anoxia/reoxygenation (A/R) cardiomyocytes were determined by qRT-PCR. After transfection with siRNA-lncRNA, AK12348, LDH release and cell apoptotic rates in normal and A/R cardiomyocytes were determined. The protein expression values of PARP and Caspase-3 were also determined by western blotting. RESULTS: The relative level of lncRNA AK12348, LDH release and cell apoptotic rate in A/R cardiomyocytes was significantly higher than that in normal cardiomyocytes. After transfection with siRNA-lncRNA AK12348, LDH release and cell apoptotic rates in A/R cardiomyocytes were reduced, while the values in normal cardiomyocytes had almost no change. The protein expression values of PARP and Caspase-3 in A/R cardiomyocytes were much higher than the Control. After knockdown of lncRNA AK12348, the values decreased. CONCLUSION: Long non-coding RNAs AK12348 could be potential therapeutic targets for the treatment of myocardial IRI.

Surgical shunts compared with endoscopic sclerotherapy for the treatment of variceal bleeding in adults with portal hypertension: a systematic review and meta-analysis.

AIM: Portal hypertension is a common complication of chronic liver disease and can cause variceal bleeding which is associated with high mortality. Choices for the treatment of variceal bleeding include surgical shunts and endoscopic sclerotherapy. The aim of this study was to compare the efficacy of surgical shunts and endoscopic sclerotherapy in treating variceal bleeding due to portal hypertension. DESIGN: Systematic review and meta-analysis. SETTING: Medline, PubMed, Cochrane and Google Scholar databases were searched until 12 February 2015, for relevant randomised control trials. Twenty studies with a total of 1540 participants were included. PATIENTS: Patients with variceal bleeding due to portal hypertension. INTERVENTIONS: Surgical shunts compared to endoscopic sclerotherapy. MAIN OUTCOME MEASURES: Rates of rebleeding, survival and hepatoencephalopathy, and length of hospital stay. RESULTS: Pooled data for 17 studies showed that the rate of rebleeding was significantly more frequent with sclerotherapy compared with surgical shunt therapy (OR 3.99, 95% CI 2.98 to 5.33, p<0.001). The sclerotherapy patient group compared with the shunt group was less likely to develop hepatoencephalopathy (15 studies: pooled OR 0.53, 95% CI 0.31 to 0.91, p=0.021) and had shorter hospital stays (pooled mean difference-4.32, 95% CI- 7.97 to -0.66, p=0.021). No significant difference in the survival rate was observed between the two groups (seven studies: OR 1.01, 95% CI 0.63 to 1.62, p=0.964). CONCLUSION: This analysis indicated that the two types of treatment have similar mortality rates but differed with respect to rebleeding rate, incidence of hepatoencephalopathy and length of hospital stay.

Drug-delivering endovascular treatment versus angioplasty in artery occlusion diseases: a systematic review and meta-analysis.

OBJECTIVE: The best management of patients with femoropopliteal and infrapopliteal artery occlusion disease is not clear. This study aimed to compare the efficacy of drug-coated balloons (DCBs) and drug-eluting stents (DESs) with percutaneous transluminal angioplasty (PTA) in patients with femoropopliteal or infrapopliteal arterial occlusive disease. METHODS: Medline, Cochrane, Embase, and Google Scholar databases were searched for randomized controlled trials from 1 January 2000 until 30 June 2016. RESULTS: Compared with PTA, significant benefits in favor of DCB and DES were found for target lesion revascularization (TLR) (OR = 0.38, 95% CI = 0.22 to 0.66, p = .001 for DCB; OR = 0.51, 95% CI = 0.32 to 0.81, p < .001 for DES). Primary patency rate was greater with DCB (p = .001) and DES (p < .001) than PTA. Compared with PTA, a significant reduction in mortality was observed in the DCB group (p = .039) but not in the DES group. Subgroup analysis found a lower rate of TLR and a higher rate of primary patency in the active group (DCB and DES) compared with the control group (PTA) in patients with femoropopliteal arterial occlusion (p ≤ .016) but not in patients with infrapopliteal arterial occlusion (p ≥ .063). Mortality was similar between active replacement and control groups both in the femoropopliteal arterial occlusion and the infrapopliteal arterial occlusion subgroups (all p > .05). CONCLUSIONS: Significantly better TLR and primary patency rate were found in the drug-delivering endovascular treatments compared with the PTA group for patients with femoropopliteal arterial occlusion but not for patients with infrapopliteal arterial occlusion.

Identification of key genes associated with the human abdominal aortic aneurysm based on the gene expression profile.

The present study was aimed at screening the key genes associated with abdominal aortic aneurysm (AAA) in the neck, and to investigate the molecular mechanism underlying the development of AAA. The gene expression profile, GSE47472, including 14 AAA neck samples and eight donor controls, was downloaded from the Gene Expression Omnibus database. The total AAA samples were grouped into two types to avoid bias. Differentially expressed genes (DEGs) were screened in patients with AAA and subsequently compared with donor controls using linear models for microarray data, or the Limma package in R, followed by gene ontology enrichment analysis. Furthermore, a protein­protein interaction (PPI) network based on the DEGs was constructed to detect highly connected regions using a Cytoscape plugin. In total, 388 DEGs in the AAA samples were identified. These DEGs were predominantly associated with limb development, including embryonic limb development and appendage development. Nuclear receptor co­repressor 1 (NCOR1), histone 4 (H4), E2F transcription factor 4 (E2F4) and hepatocyte nuclear factor 4α (HNF4A) were the four transcription factors associated with AAA. Furthermore, HNF4A indirectly interacted with the other three transcription factors. Additionally, six clusters were selected from the PPI network. The DEG screening process and the construction of an interaction network enabled an understanding of the mechanism of AAA to be gleaned. HNF4A may exert an important role in AAA development through its interactions with the three other transcription factors (E2F4, NCOR1 and H4), and the mechanism of this coordinated regulation of the transcription factors in AAA may provide a suitable target for the development of therapeutic intervention strategies.

High glucose conditions suppress the function of bone marrow-derived endothelial progenitor cells via inhibition of the eNOS-caveolin-1 complex.

The present study aimed to reveal how high glucose affects rat bone marrow-derived endothelial progenitor cells in vitro. Total mononuclear cells of bone marrow were obtained, cultured in endothelial cell growth medium-2 and identified by fluorescence microscopy. Using immunofluorescence, endothelial progenitor cells were identified by expression of VEGFR­2 as well as CD133 and were further characterized as those adherent cells which were double positive by Dil­ac­LDL uptake and FITC-UEA-1 lectin binding. The attached cells were collected and glucose was added to the culture medium at various final concentrations (11.1, 33.3 and 55.5 mmol/l). Proliferation, migration and in vitro angiogenic ability of endothelial progenitor cells were measured. The change in mRNA and protein levels of caveolin-1 and endothelial nitric oxide synthase (eNOS) were examined; in addition, nitric oxide (NO) levels in the cell medium were measured. Based on the results, with increasing glucose concentration in the medium, proliferation, migration and in vitro angiogenic capacity of the cells were reduced, whereas mRNA and protein levels of caveolin-1 gene increased gradually. The mRNA levels of the eNOS gene did not differ, but the protein expression was reduced and NO levels in the culture medium declined. In conclusion, high glucose conditions are detrimental to the function of bone marrow­derived endothelial progenitor cells in vitro, probably by damaging the eNOS-caveolin-1 complex, which results in the reduction of NO synthesis, eventually leading to the impaired function of endothelial progenitor cells.

Endovascular nitinol stenting for long occlusive disease of the superficial femoral artery in critical limb ischemia: a single-center, mid-term result.

BACKGROUND: The aim of the present study was to assess the mid-term patency rate of nitinol stent implantation in patients with long superficial femoral artery (SFA) stenosis or occlusion. This is a retrospective, single-center study. METHODS: The data of 138 patients were retrospectively assessed in our center to determine the patency rate after nitinol stenting of the SFA. MATERIALS: Data for 165 limbs from 138 patients were collected. Each limb showed a long lesion with a total occlusion of >10 cm and mean lesion length of 20.35 ± 9.46 cm (range, 10-32 cm). Nitinol self-expanding stent implantations were performed in each limb. A total of 258 stents were implanted into 165 limbs (average, 1.56 stents/limb). Each patient received clinical and ultrasound/computerized tomographic angiography/magnetic resonance angiography evaluations before the procedure and underwent clinical status evaluation and an ankle-brachial index test at discharge and at 12, 24, and 36 months thereafter. RESULTS: The initial technical success rate of revascularization was 91.51% (151/163). During follow-up, nine patients died because of myocardial infarction, cerebral infarction, and pneumonia, and 14 patients were lost to follow-up. The mean follow-up period for 150 limbs from 124 patients was 25.46 months (range, 6-51). During follow-up, 19 in-stent restenoses and 15 occlusions were diagnosed. In all, 30 re-interventions were performed, including six balloon angioplasties, three secondary cutting balloon angioplasties, 10 restenting procedures, four bypass surgeries, two bone marrow stem cell transplantations, and five limb amputations. Analysis showed the primary patency rates at 12, 24, and 36 months were 92.4%, 78.3%, and 62.1%, respectively, and the overall assisted-primary patency rates were 94.4%, 84.6%, and 75.8%, respectively. CONCLUSIONS: Nitinol self-expanding stent implantation seems to be a good choice for older patients with long SFA occlusions. Although the short- and mid-term patency results were good, more observations are needed to assess its long-term efficiency.