Down-regulating of MFN2 promotes vascular calcification via regulating RAS-RAF-ERK1/2 pathway.

BACKGROUND: Vascular calcification (VC), as a prevalent feature of atherosclerosis (AS), is a life-threatening pathological change. Mitofusin 2 (MFN2) has been reported to be down-regulated and participate in the pathogenesis of AS. Here, we explored the feasible impacts of MFN2 on VC in AS. METHODS: Atherosclerotic lesion was evaluated by Oil Red O staining. The VC was detected by Alizarin Red S staining, ALP staining, and calcium content in vascular smooth muscle cells (VSMCs) or atherosclerotic mice. The chondrocyte differentiation of VSMCs was measured by Alcian blue staining. Western blotting and qRT-PCR were used to determine the protein and mRNA expression of associated molecules. Intermolecular interaction was measured by ChIP and dual luciferase assays. RESULTS: The expression of MFN2 and E2F1 was reduced in the aorta tissues of AS patients and mice. Silencing of MFN2 drove calcification in VSMCs and aortas of atherosclerotic mice as confirmed by up-regulating RUNX2, OPG levels, and down-regulating SM22α, α-SMA levels. The chondrocyte differentiation of VSMCs was accelerated by MFN2 knockdown through inducing the expression of Aggrecan, Collagen II, and SOX9. In addition, E2F1 promoted the transcription and expression of MFN2 in VSMCs. Overexpression of MFN2 or E2F1 suppressed ox-LDL-induced VSMC calcification. Finally, MFN2 depletion enhanced VSMC calcification via activating RAS-RAF-ERK1/2 pathway. CONCLUSION: Our results suggest that silencing of MFN2 drives VC via activating RAS-RAF-ERK1/2 pathway in the progression of AS, thus MFN2 may be a therapeutic target for AS.

CircHIPK3 Regulates Vascular Smooth Muscle Cell Calcification Via the miR-106a-5p/MFN2 Axis.

Atherosclerosis is the most common arterial disease and is closely related to vascular calcification. CircHIPK3 has been implicated in atherosclerosis development, but the possible downstream regulatory mechanisms remain unclear. The levels of circHIPK3, miR-106a and MFN2 in tissues and blood samples of patients with atherosclerosis were detected by RT-qPCR. The levels of circHIPK3, miR-106a and MFN2 were detected by RT-qPCR and the expression levels of MFN2, osteogenic and cartilage differentiation marker proteins were detected by western blot in vitro. ALP staining, Alizarin Red staining, and calcium content detection evaluated the degree of osteogenic differentiation of cells. Alcian blue staining detected the level of cell cartilage differentiation. Luciferase detected the targeting relationship between circHIPK3 and miR-106a-5p, as well as miR-106a-5p and MFN2. CircHIPK3 and MFN2 were low expressed and miR-106a-5p was highly expressed in tissues and blood samples of patients with atherosclerosis, as well as vascular smooth muscle cell (VSMC) with osteogenic and cartilage differentiation. Overexpression of circHIPK3 reduced the cell mineralization and calcium content. Overexpression of circHIPK3 inhibited osteogenic differentiation by decreasing ALP activity, RUNX2, and OPG expression, and increasing SM22α and SMA level. What's more, overexpression of circHIPK3 decreased the chondrogenic differentiation by inhibiting the protein level of SOX9, aggrecan, and collagen II. CircHIPK3 targeted miR-106a-5p and miR-106a-5p targeted MFN2. MiR-106a-5p overexpression or MFN2 depletion repressed the effect of circHIPK3 overexpression on VSMC calcification. CircHIPK3 regulated osteogenic and cartilage differentiation of VSMC via miR-106a-5p/MFN2 axis, indicating a target for treating vascular calcification.

Associations of high-mobility group box 1 and receptor for advanced glycation end products with acute lung injury in patient with acute aortic dissection.

OBJECTIVE: To investigate the associations of high-mobility group box 1 and its specific receptor, receptor for advanced glycation end products with acute lung injury in patients with acute aortic dissection. METHODS: A total of 96 acute aortic dissection patients were divided into acute aortic dissection with acute lung injury group (38 cases) and acute aortic dissection without acute lung injury group (58 cases), according to partial pressure of oxygen/fraction of inspired oxygen. In addition, 44 healthy individuals were selected for the control group. The blood samples were taken. The serum high-mobility group box 1 and receptor for advanced glycation end products levels were detected by enzyme-linked immunosorbent assay, and the partial pressure of oxygen/fraction of inspired oxygen was measured. RESULTS: 24 h after admission, the high-mobility group box 1 and receptor for advanced glycation end products levels in acute aortic dissection with acute lung injury and acute aortic dissection without acute lung injury groups were significantly higher than those in the control group, respectively (p<0.05), and each index in acute aortic dissection with acute lung injury group was significantly higher than that in acute aortic dissection without acute lung injury group (p<0.05). At each time point within 96 h after admission, compared with acute aortic dissection without acute lung injury group, in acute aortic dissection with acute lung injury group, the high-mobility group box 1 and receptor for advanced glycation end products levels were increased, respectively, and the partial pressure of oxygen/fraction of inspired oxygen was decreased. The correlation analysis showed that, in acute aortic dissection patients, the high-mobility group box 1 and receptor for advanced glycation end products levels were negatively correlated with partial pressure of oxygen/fraction of inspired oxygen, respectively (p<0.05). CONCLUSIONS: The serum high-mobility group box 1 and receptor for advanced glycation end products levels may be associated with the occurrence of acute lung injury in acute aortic dissection patients. Monitoring the high-mobility group box 1 and receptor for advanced glycation end products levels can evaluate the risk of acute aortic dissection with acute lung injury.

Associations of high-mobility group box 1 and receptor for advanced glycation end products with acute lung injury in patient with acute aortic dissection

SUMMARY OBJECTIVE: To investigate the associations of high-mobility group box 1 and its specific receptor, receptor for advanced glycation end products with acute lung injury in patients with acute aortic dissection. METHODS: A total of 96 acute aortic dissection patients were divided into acute aortic dissection with acute lung injury group (38 cases) and acute aortic dissection without acute lung injury group (58 cases), according to partial pressure of oxygen/fraction of inspired oxygen. In addition, 44 healthy individuals were selected for the control group. The blood samples were taken. The serum high-mobility group box 1 and receptor for advanced glycation end products levels were detected by enzyme-linked immunosorbent assay, and the partial pressure of oxygen/fraction of inspired oxygen was measured. RESULTS: 24 h after admission, the high-mobility group box 1 and receptor for advanced glycation end products levels in acute aortic dissection with acute lung injury and acute aortic dissection without acute lung injury groups were significantly higher than those in the control group, respectively (p<0.05), and each index in acute aortic dissection with acute lung injury group was significantly higher than that in acute aortic dissection without acute lung injury group (p<0.05). At each time point within 96 h after admission, compared with acute aortic dissection without acute lung injury group, in acute aortic dissection with acute lung injury group, the high-mobility group box 1 and receptor for advanced glycation end products levels were increased, respectively, and the partial pressure of oxygen/fraction of inspired oxygen was decreased. The correlation analysis showed that, in acute aortic dissection patients, the high-mobility group box 1 and receptor for advanced glycation end products levels were negatively correlated with partial pressure of oxygen/fraction of inspired oxygen, respectively (p<0.05). CONCLUSIONS: The serum high-mobility group box 1 and receptor for advanced glycation end products levels may be associated with the occurrence of acute lung injury in acute aortic dissection patients. Monitoring the high-mobility group box 1 and receptor for advanced glycation end products levels can evaluate the risk of acute aortic dissection with acute lung injury.

IL-10 regulates the malignancy of hemangioma-derived endothelial cells via regulation of PCNA.

Hemangioma (HA) is the most common benign tumor and formed by the proliferating endothelial cells of blood vessels. Interleukins (ILs) have been reported to be critical for HA progression. Our present study found that the expression of IL-10 was decreased in HA cells and tissues as compared to their corresponding controls. Treatment with recombinant IL-10 (rIL-10) can suppress the proliferation of HA cells via suppression of proliferating cell nuclear antigen (PCNA), while over expression of PCNA can attenuate rIL-10-inhibited cell proliferation. Further, rIL-10 can decrease the promoter activity and mRNA stability of PCNA in HA cells. Mechanistically, rIL-10 can increase expression of miR-27b-3p to decrease mRNA stability of PCNA, while down regulation of YY1 is involved in rIL-10 suppressed transcription of PCNA. Collectively, IL-10 can suppress the expression of PCNA via miR-27b-3p mediated suppression of mRNA stability and YY1 mediated down regulation of transcription. It suggested that rIL-10 might be a potential therapeutic approach for HA development and progression.

miR-501 promotes hemangioma progression by targeting HOXD10.

MicroRNAs (miRNAs) are often abnormally expressed in human cancers to act as either oncogenes or tumor suppressor genes. MiRNA-501 (miR-501) has been found to be abnormally expressed in certain types of cancer, but its expression and biological role in hemangioma remain to be fully elucidated. In this study, the expression of miR-501 in hemangioma cell lines was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). The TargetScan algorithm, luciferase activity reporter assay, and Western blot analysis were conducted to validate homeobox D10 (HOXD10) as a direct target of miR-501. The results revealed that miR-501 expression was upregulated in hemangioma cell lines. Downregulation of miR-501 inhibited hemangioma cell proliferation, cell cycle progression, colony formation, migration, and invasion in vitro. Bioinformatics analysis indicated that HOXD10 was a putative target of miR-501. In addition, in a luciferase reporter system, it was confirmed that HOXD10 is a direct target of miR-501. It was also demonstrated HOXD10 downregulation reversed the effects of the miR-501 inhibitor on hemangioma cell activities. These findings indicated that miR-501 targeted HOXD10 to promote hemangioma cell processes, suggesting that miR-501 has an oncogenic role in the pathogenesis of hemangioma.

Infected Abdominal Aortic Aneurysms Treated with Extra-anatomic Prosthesis Bypass in the Retroperitoneum.

BACKGROUND: Infected abdominal aortic aneurysms (iAAAs) are rare but life-threatening diseases. The purpose of the present study was to report our experience of extra-anatomic prosthesis bypass in the retroperitoneum as a treatment for iAAAs. METHODS: Data of 8 consecutive patients diagnosed with iAAAs and treated by an extra-anatomic prosthesis bypass in the retroperitoneum were retrospectively collected. Operative details were as follows: one side of the retroperitoneal space was selected to build a track, and a bifurcated expanded polytetrafluoroethylene prosthesis was placed through the track. The proximal end of the prosthesis was sutured with the normal segment of abdominal aorta proximal to the infected aneurysm by end-to-end anostomosis. The 2 distal ends of the prosthesis were, respectively, sutured with the external iliac artery distal to the aneurysm. The anastomoses were then consolidated with the nearby connective tissue. After the closure of the retroperitoneum, the infected aneurysm was incised, and the infected tissue was debrided. Drainage tubes were placed in the aneurysm sac, which was packed with an omentum flap. All patients received perioperative antibiotic therapy for a period of time. All 8 patients were regularly followed up by outpatient observation. RESULTS: Eight patients with iAAAs underwent an extra-anatomic prosthesis bypass in the retroperitoneum and debridement of the infected aneurysm. An emergency operation was performed for 1 patient who underwent concomitant gastrointestinal procedures for aortoduodenal fistula. All 8 patients were definitively diagnosed by one or more sequential computed tomography scans combined with other methods. The blood or tissue cultures of all cases were positive in the perioperative period, with Salmonella (5 cases) being the most common pathogens. Other pathogens included Burkholderia pseudomallei (2 cases) and Escherichia coli (1 case). All patients survived and were discharged in 4-5 weeks after their operations. All patients were free from graft infection during the follow-up period. CONCLUSIONS: The extra-anatomic prosthesis bypass in the retroperitoneum for treating iAAAs was safe and effective. Our experience with the procedure may provide a new approach for the treatment of this disease.