Empagliflozin inhibits neointimal hyperplasia through attenuating endothelial-to-mesenchymal transition via TAK-1/NF-κB pathway.

OBJECTIVE: To investigate whether empagliflozin could prevent injury-induced vascular neointimal hyperplasia and to further explore its mechanism. METHODS: Male C57BL/6J mice were divided into two groups with or without the empagliflozin treatment, and carotid ligation injury was performed to induce neointimal hyperplasia. The injured carotid arteries were collected for Western blotting (WB), histology and immunofluorescence analysis after four weeks. The inflammatory responses were analyzed by qRT-PCR to detect the inflammatory gene mRNA expression. To further explore its mechanism, HUVECs were treated with TGFß-1 to induce EndMT followed by empagliflozin or vehicle treatment in vitro. A23187 (Calcimycin), an agonist of NF-κB signaling was used in the experiment. RESULTS: The wall thickness and the neointima area was significantly reduced in the empagliflozin treatment group on day 28 after artery ligation. The Ki-67 positive cells were 28.33 ± 12.66% and 48.83 ± 10.41% in the empagliflozin-treated group and control group, respectively (P < 0.05). The mRNA expression levels of the inflammatory genes and inflammatory cells were decreased in the empagliflozin treatment group, as well as the MMP2 and MMP9. Meanwhile, empagliflozin can significantly reduce the migratory ability of inflammatory-treated HUVECs. The CD31 was increased in the TGFß1+empagliflozin group, whereas the FSP-1, phosphorylation of TAK-1 (p-TAK-1) and phosphorylation of NF-κB (p- NF-κB) expression level were decreased, compared to the control group without empagliflozin treatment. However, the expression level of FSP-1 and p-NF-κB were reversed after co-treatment with A23187, whereas the p-TAK-1 expression level was without any significant difference. CONCLUSION: Empagliflozin inhibits the inflammation-induced EndMT via the TAK-1/NF-κB signaling pathway.

Long-term outcome of spontaneous isolated superior mesenteric artery dissection in different angiographic types.

OBJECTIVE: This study aimed to compare the follow-up and outcomes of spontaneous isolated superior mesenteric artery dissection (SISMAD) in different angiographic types and to determine the optimal therapeutic options for SISMAD patients. METHODS: This is a retrospective study of 61 SISMAD patients between December 2010 and January 2019 in a single center. Data analysis consisted of demographics, clinical data, radiology review, treatment, follow-up, and outcomes. RESULTS: A total of 61 SISMAD patients were reviewed in this study. Median age was 53 (quartile, 47.5-63.0), 90.2% were males with hypertension (50.8%), dyslipidaemia (54.1%), and smoking history (60.7%). Among all, 43 patients underwent periodic follow-up of computed tomography (CT) angiography for follow-up analysis. 11 (25.6%) patients showed "No Change" during follow-up, including 6 type I patients. 23 patients (53.5%) were "Partially Remodelled" and 18 of them were type II patients. 7 "Completely Remodelled" patients (16.3%) were all in type II group. Two type III patients (4.6%) died after the emergent surgical intervention within 30 days. CONCLUSIONS: Different SISMAD angiographic types present with variant progression. Type I SISMAD may be inclined to remain "unchanged." Type II SISMAD shows a clear trend to remodeling, especially type IIb patients. The progression of type III SISMAD varies in the extent of collateral bypasses.

A splice site mutation in the TSEN2 causes a new syndrome with craniofacial and central nervous system malformations, and atypical hemolytic uremic syndrome.

Recessive mutations in the genes encoding the four subunits of the tRNA splicing endonuclease complex (TSEN54, TSEN34, TSEN15, and TSEN2) cause various forms of pontocerebellar hypoplasia, a disorder characterized by hypoplasia of the cerebellum and the pons, microcephaly, dysmorphisms, and other variable clinical features. Here, we report an intronic recessive founder variant in the gene TSEN2 that results in abnormal splicing of the mRNA of this gene, in six individuals from four consanguineous families affected with microcephaly, multiple craniofacial malformations, radiological abnormalities of the central nervous system, and cognitive retardation of variable severity. Remarkably, unlike patients with previously described mutations in the components of the TSEN complex, all the individuals that we report developed atypical hemolytic uremic syndrome (aHUS) with thrombotic microangiopathy, microangiopathic hemolytic anemia, thrombocytopenia, proteinuria, severe hypertension, and end-stage kidney disease (ESKD) early in life. Bulk RNA sequencing of peripheral blood cells of four affected individuals revealed abnormal tRNA transcripts, indicating an alteration of the tRNA biogenesis. Morpholino-mediated skipping of exon 10 of tsen2 in zebrafish produced phenotypes similar to human patients. Thus, we have identified a novel syndrome accompanied by aHUS suggesting the existence of a link between tRNA biology and vascular endothelium homeostasis, which we propose to name with the acronym TRACK syndrome (TSEN2 Related Atypical hemolytic uremic syndrome, Craniofacial malformations, Kidney failure).

Self-Radiopaque Markers Guiding Physician-Modified Fenestration (S-Fenestration) in Aortic Arch Endovascular Repair.

Backgrounds and Objectives: Thoracic endovascular aortic repair (TEVAR) has currently become the "first-line choice" for descending aortic pathologies. For pathologies located at the aortic arch, TEVAR with physician-modified fenestration (PMF) has been gained popularity as an alternative choice. However, stent fenestration is an experience-dependent technique and comes with possible adverse events such as misalignment. This study aims to introduce the self-radiopaque PMF (SF), which uses the radiopaque marker as a guiding indicator. Methods: This is a single-center retrospective study of 125 patients who underwent the SF-TEVAR in Second Xiangya Hospital from December 2015 to December 2020. Data include basic clinical information and technique records of SF-TEVAR with follow-up results. Results: According to the SF-TEVAR protocol, we have performed the procedures on 125 patients and obtained an instant success rate of 98.4%. A total of 140 aortic stent-grafts and 44 bridging stents have been implanted in this study. The operation time is 64.6 ± 19.3 min, X-ray exposure time (from first digital subtraction angiography (DSA) to last DSA) is 25.6 ± 14.3 min, and contrast volume is 82.2 ± 22.6 ml. The success rate of PMF alignment is 98.4%. One bailout stent-graft was implanted into the left subclavian artery (LSA) by the chimney technique (0.8%). One fenestration was successfully and immediately corrected after misalignment (0.8%). Large simultaneous fenestration was performed in six patients (4.8%) for the left common carotid artery (LCCA) and LSA and in two patients (1.6%) for IA, LCCA, and LSA. One hundred twenty-two out of 125 patients' LSAs have been kept patent by the technique during the follow-up. The bridging stent group consists of 44 patients who received LSA stents, while the non-bridging stent group includes the other 81 patients. Type I endoleak has occurred in seven patients (5.6%) 1 week after the procedure. During follow-up (23 ± 18 months), survival rate is 95.7% and branch artery patent rate is 97.4%. Conclusions: The SF-TEVAR technique, which utilizes the radiopaque marker in stent-graft as an indication for PMF in TEVAR, seems a likely safe, effective, and efficient procedure that brings acceptable survival rate and branch artery patency rate. SF-TEVAR serves as a progressive alternative method to keep the branch artery patent in aortic arch endovascular reconstruction.

TRIP13 modulates protein deubiquitination and accelerates tumor development and progression of B cell malignancies.

Multiple myeloma (MM), a terminally differentiated B cell malignancy, remains difficult to cure. Understanding the molecular mechanisms underlying the progression of MM may identify therapeutic targets and lead to a fundamental shift in treatment of the disease. Deubiquitination, like ubiquitination, is a highly regulated process, implicated in almost every cellular process. Multiple deubiquitinating enzymes (DUBs) have been identified, but their regulation is poorly defined. Here, we determined that TRIP13 increases cellular deubiquitination. Overexpression of TRIP13 in mice and cultured cells resulted in excess cellular deubiquitination by enhancing the association of the DUB USP7 with its substrates. We show that TRIP13 is an oncogenic protein because it accelerates B cell tumor development in transgenic mice. TRIP13-induced resistance to proteasome inhibition can be overcome by a USP7 inhibitor in vitro and in vivo. These findings suggest that TRIP13 expression plays a critical role in B cell lymphoma and MM by regulating deubiquitination of critical oncogenic (NEK2) and tumor suppressor (PTEN, p53) proteins. High TRIP13 identifies a high-risk patient group amenable to adjuvant anti-USP7 therapy.

Loss of diacylglycerol kinase ε causes thrombotic microangiopathy by impairing endothelial VEGFA signaling.

Loss of function of the lipid kinase diacylglycerol kinase ε (DGKε), encoded by the gene DGKE, causes a form of atypical hemolytic uremic syndrome that is not related to abnormalities of the alternative pathway of the complement, by mechanisms that are not understood. By generating a potentially novel endothelial specific Dgke-knockout mouse, we demonstrate that loss of Dgke in the endothelium results in impaired signaling downstream of VEGFR2 due to cellular shortage of phosphatidylinositol 4,5-biphosphate. Mechanistically, we found that, in the absence of DGKε in the endothelium, Akt fails to be activated upon VEGFR2 stimulation, resulting in defective induction of the enzyme cyclooxygenase 2 and production of prostaglandin E2 (PGE2). Treating the endothelial specific Dgke-knockout mice with a stable PGE2 analog was sufficient to reverse the clinical manifestations of thrombotic microangiopathy and proteinuria, possibly by suppressing the expression of matrix metalloproteinase 2 through PGE2-dependent upregulation of the chemokine receptor CXCR4. Our study reveals a complex array of autocrine signaling events downstream of VEGFR2 that are mediated by PGE2, that control endothelial activation and thrombogenic state, and that result in abnormalities of the glomerular filtration barrier.

Short-term results in canines of novel stent-graft design for chimney technique in TEVAR.

INTRODUCTION: Parallel stent-stent grafting is a major endovascular technique used to preserve the supra-aortic branches during thoracic endovascular aortic repair (TEVAR) of aortic pathologies involving the aortic arch. The short- and mid-term results of this technique are satisfactory; however, endoleak remains a major concern. Thus, here we designed a new chimney stent-graft to decrease the endoleak rate. AIM: To testify the feasibility and safety of the new chimney stent-graft system in a canine model. MATERIAL AND METHODS: Six Labrador retrievers were used. Pre-operative data were collected and all operations were performed under general anesthesia. The main and chimney stent-grafts were implanted through the abdominal aorta and left subclavian artery approaches, respectively. Completion digital subtraction angiography (DSA) was performed to confirm the immediate outcomes. All dogs were fed separately for 6 months and sacrificed after aortic angiography. The thoracic aorta and the main and chimney stent-grafts were harvested for histopathologic examination. RESULTS: No complications were found in follow-up DSA. All branch arteries were patent. Inflammatory responses were observed around the stent-grafts in 3 experimental animals, and slight hyperplasia was observed in the surrounding tissues compared with the normal vessels. There was no mural thrombus in the stent, endothelial cells were noted on the inner surface of the stent, and thrombus was formed in the outer skirt and gutter area. The histopathologic examinations revealed similar results to those of gross necropsy observations. CONCLUSIONS: This study demonstrated the feasibility and safety of the Longuette stent-graft and the first to report a revised stent-graft specific for chimney technique.

Innate Immune Signaling Contributes to Tubular Cell Senescence in the Glis2 Knockout Mouse Model of Nephronophthisis.

Nephronophthisis (NPHP), the leading genetic cause of end-stage renal failure in children and young adults, is a group of autosomal recessive diseases characterized by kidney-cyst degeneration and fibrosis for which no therapy is currently available. To date, mutations in >25 genes have been identified as causes of this disease that, in several cases, result in chronic DNA damage in kidney tubular cells. Among such mutations, those in the transcription factor-encoding GLIS2 cause NPHP type 7. Loss of function of mouse Glis2 causes senescence of kidney tubular cells. Senescent cells secrete proinflammatory molecules that induce progressive organ damage through several pathways, among which NF-κB signaling is prevalent. Herein, we show that the NF-κB signaling is active in Glis2 knockout kidney epithelial cells and that genetic inactivation of the toll-like receptor (TLR)/IL-1 receptor or pharmacologic elimination of senescent cells (senolytic therapy) reduces tubule damage, fibrosis, and apoptosis in the Glis2 mouse model of NPHP. Notably, in Glis2, Tlr2 double knockouts, senescence was also reduced and proliferation was increased, suggesting that loss of TLR2 activity improves the regenerative potential of tubular cells in Glis2 knockout kidneys. Our results further suggest that a combination of TLR/IL-1 receptor inhibition and senolytic therapy may delay the progression of kidney disease in NPHP type 7 and other forms of this disease.

Contrast-Induced Kidney Nephropathy in Thoracic Endovascular Aortic Repair: A 2-Year Retrospective Study in 470 Patients.

We identified changes in renal function in patients who underwent thoracic endovascular aortic repair (TEVAR) and the factors that may influence renal function. Information on 470 consecutive patients was collected. Kidney function and contrast volume were recorded. Unpaired t test, Spearman correlation, and logistic regression were used for statistical analysis. A Kaplan-Meier curve helped clarify our follow-up findings. Mean contrast volume was 90.5 ± 21.2 mL. The change in serum creatinine was significantly correlated with (1) preexisting renal pathology (P = .033) and (2) aortic dissection (AD) involving the renal arteries (P = .019). The change in serum urea nitrogen (ΔBUN) was only significantly correlated with AD involving the renal arteries (P = .0348). Contrast volume (P = .036, odds ratio = 1.010, 95% confidence interval: 1.001-1.019) was a risk factor for contrast-induced nephropathy (CIN) after TEVAR. Survival rates and renal failure rates among no CIN, CIN, and CIN-acute kidney injury groups at longest 27 months follow-up were significantly different. Creatinine and BUN were generally elevated post-TEVAR. Contrast-induced nephropathy post-TEVAR may correlate with renal comorbidities and renal artery involvement. Contrast volume is risk factor for CIN after TEVAR. More attention needs to be paid to patient renal function during follow-up.

Epithelial innate immunity mediates tubular cell senescence after kidney injury.

Acute kidney injury (AKI) is a common clinical condition of growing incidence. Patients who suffer severe AKI have a higher risk of developing interstitial fibrosis, chronic kidney disease, and end-stage renal disease later in life. Cellular senescence is a persistent cell cycle arrest and altered gene expression pattern evoked by multiple stressors. The number of senescent cells increases with age and even in small numbers these cells can induce chronic inflammation and fibrosis; indeed, in multiple organs including kidneys, the accumulation of such cells is a hallmark of aging. We hypothesized that cellular senescence might be induced in the kidney after injury and that this might contribute to progressive organ fibrosis. Testing this hypothesis, we found that tubular epithelial cells (TECs) in mice senesce within a few days of kidney injury and that this response is mediated by epithelial Toll-like and interleukin 1 receptors (TLR/IL-1R) of the innate immune system. Epithelial cell-specific inhibition of innate immune signaling in mice by knockout of myeloid differentiation 88 (Myd88) reduced fibrosis as well as damage to kidney tubules, and also prevented the accumulation of senescent TECs. Importantly, although inactivation of Myd88 after injury ameliorated fibrosis, it did not reduce damage to the tubules. Selectively induced apoptosis of senescent cells by two different approaches only partially reduced kidney fibrosis, without ameliorating damage to the tubules. Our data reveal a cell-autonomous role for epithelial innate immunity in controlling TEC senescence after kidney injury, and additionally suggest that early therapeutic intervention is required for effective reduction of long-term sequelae of AKI.

Atorvastatin regulates pericardial patch healing via the microRNA140-ADAM10-ephrinB2 pathway.

Background: Pericardial patches are frequently used in vascular surgery to close arteriotomies. The early healing of these patches is mediated by attraction of CD34 and ephrinB2-positive cells. Atorvastatin is a commonly used statin drug that promotes healing of cardiovascular injury. We hypothesized that atorvastatin attracts ephrinB2-positive cells by regulating the microRNA140-ADAM10-ephrinB2 pathway during patch healing in the arterial environment. Methods: Pericardial patches were used to close an infra-renal aortic arteriotomy in Wistar rats (male, 200-400 g). Atorvastatin was given to rats at a daily dose of 0 mg, 2.5 mg, 5 mg or 10 mg. Patches were harvested at 1 or 4 weeks and analyzed by histology, immunohistochemistry, immunofluorescence, western blot and qPCR. Result: Animals treated with atorvastatin showed a higher number of infiltrating cells and a thicker patch neointima than the control animals. Furthermore, ADAM10 protein expression decreased (P<0.01) and ephrinB2 expression increased (P<0.01) in time- and atorvastatin dose-dependent manner. Similarly, ADAM10 mRNA expression decreased (P<0.01), while the expression of ephrinB2 mRNA and miR-140 mRNA expression increased (P<0.01; P<0.01) in a time- and dose-dependent manner. Conclusion: Atorvastatin regulates neointimal growth after pericardial patch angioplasty; atorvastatin is associated with infiltration of ephrinB2-positive cells, diminished ADAM10 expression, and increased ephrinB2 and miR-140 expression. These results suggest new mechanisms for regulating neointimal formation after vascular procedures. Clinical relevance: This study may help physicians to know more healing mechanism after pericardial patch angioplasty. Further, it may reveal some mechanism that how atorvastatin play roles in endothelium repair of the cardiovascular system.

Comparison of clinical outcomes of endovascular versus open revascularization for chronic mesenteric ischemia: a meta-analysis.

BACKGROUND: The purpose of this study is to compare the clinical outcomes of endovascular versus open revascularization for chronic mesenteric ischemia (CMI). METHODS: Published studies that investigated endovascular versus open revascularization for CMI were identified, and meta-analysis was used for statistical analysis. RESULTS: Eight studies were analyzed by meta-analysis method, cumulative 569 cases were included. Endovascular treatments were performed in 209 cases, and open repairs were performed in 360 cases. Meta-analysis showed that there was no difference in 30-day mortality and 3-year cumulative survival rate between the endovascular group and the open group (P = 0.55 and P = 0.56); compared with the open revascularization group, the endovascular revascularization group resulted in significantly lower rate of in-hospital complication (P = 0.002), while recurrence rate within 3 years after revascularization was significantly greater in the endovascular revascularization group (P < 0.00001). CONCLUSION: Endovascular treatment offers a benefit of lower in-hospital complication rate, but a greater recurrence rate within 3 years after revascularization compared with the open revascularization, and both groups have similar 30-day mortality and 3-year cumulative survival rate.