Osteopontin (OPN) exerts pro-inflammatory effect and is associated with the development of abdominal aortic aneurysm (AAA). However, the molecular mechanism underlying this association remains obscure. In the present study, we compared gene expression profiles of AAA tissues using microarray assay, and found that OPN was the highest expressed gene (>125-fold). Furthermore, the expression of LC3 protein and autophagy-related genes including Atg4b, Beclin1/Atg6, Bnip3, and Vps34 was markedly upregulated in AAA tissues. To investigate the ability of OPN to stimulate autophagy as a potential mechanism involved in the pathogenesis of this disease, we treated vascular smooth muscle cells (SMCs) with OPN, and found that OPN significantly increased the formation of autophagosomes, expression of autophagy-related genes and cell death, whereas blocking the signal by anti-OPN antibody markedly inhibited OPN-induced autophagy and SMC death. Furthermore, inhibition of integrin/CD44 and p38 MAPK signaling pathways markedly abrogated the biological effects of OPN on SMCs. These data for the first time demonstrate that OPN sitmulates autophagy directly through integrin/CD44 and p38 MAPK-mediated pathways in SMCs. Thus, inhibition of OPN-induced autophagy might be a potential therapeutic target in the treatment of AAA disease. J. Cell. Physiol. 227: 127-135, 2012. © 2011 Wiley Periodicals, Inc.
Intravenous leiomyomatosis (IVL) is a rare benign tumor. The study aimed to assess outcomes of patients treated surgically for IVL.Between November 2002 and January 2015, 76 patients were treated for IVL. The stage of IVL was evaluated preoperatively by echocardiography and enhanced computerized tomography (CT) scan, and graded into 4 stages according to intravascular tumor progression. We recorded age, lower limb edema before surgery, surgical parameters, and hospitalization expenses. Patients were followed up every 6 months and tumor recurrence was assessed by CT and ultrasound. Patients were followed up for a mean of 4.5 ± 2.5 years (range 1–13 years) and there was no operative, hospital, or long-term mortality or were lost to follow-up.The rate of lower extremity edema, amount of blood loss, postoperative transfusion, length of intensive care unit (ICU) stay, postoperative hospitalization, and hospitalization expenses differed significantly between patients at different presurgery stages. Tumors recurred in 4 of 7 patients with stage I IVL that opted for surgery that preserved the ovaries and uterus. No recurrence was observed in patients graded stage II or more, in all of which the uterus and ovaries were removed. Recurrence was observed in only 4 of 76 cases of IVL, all of whom opted for surgery that spared the ovaries and uterus.Different surgical strategies should be decided based on the staging to completely remove the tumor and ensure the safety of patients. Removal of both ovaries is necessary for inhibiting tumor growth and avoiding recurrence.
Background Abdominal aortic aneurysm (AAA) is the full thickness dilation of the abdominal aorta. However, few effective medical therapies are available. Thus, elucidating the molecular mechanism of AAA pathogenesis and exploring the potential molecular target of medical therapies for AAA is of vital importance. Methods Three expression datasets (GSE7084, GSE47472 and GSE57691) were downloaded from the Gene Expression Omnibus (GEO). These datasets were merged and then normalized using the “sva” R package. Differential expressed gene (DEG) analysis and weighted gene co-expression network analysis (WGCNA) were conducted. We compared the co-expression patterns between AAA and normal conditions, and hub genes of each functional module were identified. DEGs were mapped to co-expression network under AAA condition and a DEG co-expression network was generated. Crucial genes were identified using molecular complex detection (MCODE) (a plugin in Cytoscape). Results In our study, 6 and 10 gene modules were detected for the AAA and normal conditions, respectively, while 143 DEGs were screened. Compared to the normal condition, genes associated with immune response, inflammation and muscle contraction were clustered in three gene modules respectively under the AAA condition; the hub genes of the three modules were MAP4K1, NFIB and HPK1, respectively. A DEG co-expression network with 102 nodes and 303 edges was identified, and a hub gene cluster with 10 genes from the DEG co-expression network was detected. YIPF6, RABGAP1, ANKRD6, GPD1L, PGRMC2, HIGD1A, GMDS, MGP, SLC25A4 and FAM129A were in the cluster. The expression levels of these 10 genes showed potential diagnostic value. Conclusion Based on WGCNA, we detected 6 modules under the AAA condition and 10 modules in the normal condition. Hub genes of each module and hub gene clusters of the DEG co-expression network were identified. These genes may act as potential targets for medical therapy and diagnostic biomarkers. Further studies are needed to elucidate the detailed biological function of these genes in the pathogenesis of AAA.
The aim of this study was to investigate the safety and effectiveness of endovascular stenting for extracranial carotid artery aneurysms (ECAAs) and evaluate the mid-term outcomes.Twelve consecutive symptomatic patients (mean age 43.8 ± 14.9 years; 8 men) with ECAAs who were treated with endovascular stenting between 1997 and 2015 were retrospectively analyzed. Clinical follow-up data including symptoms and neurological events were obtained from outpatient records. Imaging follow-up with duplex ultrasound and/or computed tomographic angiography (CTA) was performed to examine the aneurysm obliteration and patency of the stents at 3, 6, 12 months and yearly thereafter.A total of 5 true aneurysms and 7 pseudoaneurysms were included in our series. Neurological symptoms (n = 5, 41.7%) and a pulsatile neck mass (n = 5, 41.7%) were the most common presenting symptoms. Endovascular stenting procedures were technically successful in all cases; 3 patients received bare stents, and 9 patients received covered stents. No perioperative neurologic or cardiopulmonary complications occurred. Over a period of follow-ups (mean 21.8 ± 25.1 months), all patients were alive and free from neurological or other adverse events. All aneurysms were completely excluded except for 1 patient who was exposed to a residual medium leaking into the aneurysm sac. No reintervention was performed in this specific patient because aneurysm growth or significant clinical symptoms did not occur. Recurrent restenosis assessed by CTA imaging at 12 months occurred in 1 (8.3%) patient in our series. Target lesion revascularization for this hemodynamic restenosis was treated with placement of an additional stent.In our series, endovascular stenting for ECAAs was found to be safe, effective, and proved to have promising mid-term results. Although long-term results need to be further explored, advantages including less procedure-related complications and a shorter recovery time make endovascular stenting an attractive option for ECAAs, especially for the patients who are unfit for traditional open surgery.
Abdominal aortic aneurysm (AAA) is a life-threatening aortic disease in the elderly. Activation of Notch1 pathway plays a critical role in the development of AAA, but the underlying mechanisms remain poorly understood. In the present study, we explored the mechanisms by which Notch1 activation regulates angiotensin II (Ang II)-induced AAA formation and evaluated the therapeutic potential of a new Notch γ-secretase inhibitor, dibenzazepine (DBZ), for the treatment of AAA. Apolipoprotein E knockout (Apo E−/−) mice infused for 4 weeks with Ang II (1000 ng/kg/min, IP) using osmotic mini-pumps were received an intraperitoneal injection of either vehicle or 1 mg/kg/d DBZ. Notch1 signaling was activated in AAA tissue from both Ang II-infused Apo E−/− mice and human undergoing AAA repair in vivo, with increased expression of Notch intracellular domain (NICD) and its target gene Hes1, and this effect was effectively blocked by DBZ. Moreover, infusion of Ang II markedly increased the incidence and severity of AAA in Apo E−/− mice. In contrast, inhibition of Notch activation by DBZ prevented AAA formation in vivo. Furthermore, DBZ markedly prevented Ang II-stimulated accumulation of macrophages and CD4+ T cells, and ERK-mediated angiogenesis, simultaneously reversed Th2 response, in vivo. In conclusion, these findings provide new insight into the multiple mechanisms of Notch signaling involved in AAA formation and suggest that γ-secretase inhibitor DBZ might be a novel therapeutic drug for treating AAAS.
Abdominal aortic aneurysm (AAA) is a leading cause of sudden death in aged people. Activation of ubiquitin proteasome system (UPS) plays a critical role in the protein quality control and various diseases. However, the functional role of UPS in AAA formation remains unclear. In this study, we found that the proteasome activities and subunit expressions in AAA tissues from human and angiotensin II (Ang II)-infused apolipoprotein E knockout (Apo E−/−) mice were significantly increased. To investigate the effect of proteasome activation on the AAA formation, Apo E−/− mice were cotreated with bortezomib (BTZ) (a proteasome inhibitor, 50 μg/kg, 2 times per week) and Ang II (1000 ng/kg/min) up to 28 days. Ang II infusion significantly increased the incidence and severity of AAA in Apo E−/− mice, whereas BTZ treatment markedly inhibited proteasome activities and prevented AAA formation. Furthermore, BTZ treatment significantly reduced the inflammation, inhibited the metal matrix metalloprotease activity, and reversed the phenotypic SMC modulation in AAA tissue. In conclusion, these results provide a new evidence that proteasome activation plays a critical role in AAA formation through multiple mechanisms, and suggest that BTZ might be a novel therapeutic target for treatment of AAA formation.
Background/Aims: GLP-1 and ghrelin are common appetite-regulating hormones. Both have multiple functions beyond metabolic regulation. However, the effects of GLP-1 and ghrelin on endothelial biology are not fully understood. Here, we investigate the roles of GLP-1 and ghrelin in microvascular endothelial apoptosis and senescence. Methods: Human microvascular endothelial cells (HMECs) were exposed to high glucose/high lipid (HG/HL) conditions and treated with GLP-1 or ghrelin. Cellular apoptosis, senescence, and mitochondrial function were measured. In addition, the MAPK and Akt signaling pathways were examined. Results: Both GLP-1 and ghrelin treatment decreased the number of TUNEL-positive cells and inhibited caspase-3 and PARP cleavage and mitochondrial dysfunction in HG/HL-exposed HMECs. GLP-1, but not ghrelin decreased the number of β-galactosidase (β-gal)-positive cells. Furthermore, GLP-1 and ghrelin inhibited ERK1/2, JNK1/2, and p38 signaling. GLP-1 suppressed Akt signaling, but ghrelin had no effect. Moreover, JNK1/2 and p38 inhibitors, but not ERK1/2 and Akt inhibitors, decreased the number of TUNEL-positive cells. Additionally, only the Akt inhibitor decreased the number of β-gal-positive cells. Conclusion: These results demonstrate that GLP-1 and ghrelin inhibit mitochondrial dysfunction under HG/HL conditions, and suppress endothelial apoptosis via inhibiting JNK1/2 and p38 signaling; moreover, GLP-1 alleviates endothelial senescence via inactivating Akt signaling.
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