Zongli Ren

Transforming growth factor-β1 induces matrix metalloproteinase-9 expression in rat vascular smooth muscle cells via ROS-dependent ERK-NF-κB pathways.

Both matrix metalloproteinase-9 (MMP9) and transforming growth factors-β1 (TGF-β1) are the important factors in the pathogenesis of the aortic aneurysm (AA) and aortic dissection (AD). Recent studies have shown that inhibition of reactive oxygen species (ROS) production, extracellular signal–regulated kinase 1/2(ERK1/2) or NF-κB pathways is able to suppress aneurysm formation. The median layers of arterial walls are mainly the vascular smooth muscle cells (VSMCs), while the pathogenesis of AA and AD is closely related to the changes in the median layer structure. Thus, we investigated the molecular mechanisms underlying TGF-β1-induced MMP-9 expression in VSMC, the involvement of intracellular ROS and signaling molecules, including ERK1/2 and NF-κB. Rat vascular smooth muscle cells (A7r5) were used. MMP-9 expression was analyzed by gelatin zymography, western blot and RT-PCR. The involvement of intracellular ROS and signaling molecules including ERK1/2 and NF-κB in the responses was investigated using reactive oxygen scavenger N-acetylcysteine (NAC) and pharmacological inhibitors (U0126 and BAY11-7082), determined by ROS testing and western blot testing for their corresponding proteins. TGF-β1 induces MMP-9 expression via ROS-dependent signaling pathway. ROS production leads to activation of ERK1/2 and then activation of the NF-κB transcription factor. Activated NF-κB turns on transcription of the MMP-9 gene. The process in which TGF-β1 induces MMP9 expression involves the ROS-dependent ERK–NF-κB signal pathways in VSMC. This discovery raises a new regulation pathway in the VSMC, and it shows the potential to help to find a new solution to treating aortic aneurysm and aortic dissection.

Which cannulation (axillary cannulation or femoral cannulation) is better for acute type A aortic dissection repair? A meta-analysis of nine clinical studies

There is a trend towards using the axillary artery cannulation (AXC) site for cardiopulmonary bypass surgery in patients requiring acute type A aortic dissection (AAD) repair. However, AXC has not been established as a routine procedure, because there is controversy about its clinical advantage when compared with femoral artery cannulation (FAC). This meta-analysis assesses major short-term outcomes in patients undergoing acute AAD repair with AXC or FAC using non-randomized retrospective studies dating from 1992 to 2011 comparing AXC and FAC for major outcomes. Outcomes of interest were short-term mortality, neurological dysfunction and malperfusion. The fixed-effects model was used. Sensitivity and heterogeneity were analysed. Analysis of nine non-randomized studies comprising 715 patients [AXC, 359 (50.2%) and FAC, 356 (49.8%)] showed a significantly lower incidence of short-term mortality in the AXC group [odds ratio, 0.25, 95% confidence interval (CI) (0.15, 0.42), χ(2) = 7.23, P < 0.01]. The pattern of incidence of neurological dysfunction among the AXC group [odds ratio, 0.46, 95% CI (0.29, 0.72), χ(2) = 9.01, P < 0.01] was similar. The incidence of malperfusion did not differ [odds ratio, 0.84, 95% CI (0.37, 1.90), χ(2) = 2.25, P = 0.67]. Because no study was a randomized trial, our results are more uncertain than indicated by the 95% CI. Nevertheless, AXC seems to give better short-term mortality and neurological dysfunction rates than FAC.

Outcomes of Surgical versus Balloon Angioplasty Treatment for Native Coarctation of the Aorta: A Meta-Analysis

BACKGROUND Native coarctation of the aorta (COA) accounts for 5-7% of congenital heart disease. Open surgical treatment was the only choice until balloon angioplasty (BA) treatment was introduced as an alternative therapy for COA in the 1980s. BA treatment was thought to be a less invasive and potentially safer technique, and has been used on numerous patients. But as has been reported during the past 30 years, the risk of aneurysm formation and recoarctation existed in either of those 2 procedures. Unfortunately, follow-up for either type of treatment has been limited, making it difficult to draw any meaningful conclusions as to which treatment option is superior. Our objective was to compare results of 2 therapeutic modalities to treat native COA: BA without stent implantation and surgery. METHODS We performed a meta-analysis of controlled trials of surgical versus BA treatment for native COA. MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, CINAHL, Web of Science, and the Chinese Biomedical Database of clinical trials were searched using PubMed and OVID. Controlled trials in which patients with COA were assigned to surgical repair or BA treatment were included. For each outcome, we evaluated the quality of the evidence with reference to the Grading of Recommendations Assessments, Development, and Evaluation criteria. We used RevMan 5.1 software (The Nordic Cochrane Centre, Copenhagen, Denmark) to analyze the data. RESULTS A literature search yielded 9 comparable studies, for a total of 623 patients, of whom 378 and 245 were assigned to surgery and BA. Meta-analysis of these studies showed no significant difference in postintervention gradient (inverse variance fixed mean difference: 1.44 [95% CI: -1.16 to 4.04]), midterm recoarctation (Mantel-Haenszel [M-H] random odds ratio [OR]: 0.24 [95% CI: 0.04-1.58]), and long-term recoarctation (M-H fixed OR: 0.61 [95% CI: 0.34-1.11]). BA reduces the risk of severe complications (M-H fixed OR: 2.67 [95% CI: 1.37-5.21]; P < 0.001) but increases the risk of short-term recoarctation (M-H fixed OR: 0.25 [95% CI]: 0.12-0.54]; P < 0.001) and aortic aneurysm formation (M-H fixed OR: 0.12 [95% CI]: 0.04-0.34]; P < 0.001). CONCLUSIONS BA provides immediate results comparable to surgery and reduces invasion, but it does not provide better results compared with surgery when considering medium- and long-term complications and even increases the incidence of aneurysm formation.

Highly expressed S100A12 in aortic wall of patients with DeBakey type I aortic dissection could be a promising marker to predict perioperative complications.

BACKGROUND Thoracic aortic dissection (TAD) is a catastrophic acute disease with a high postoperative mortality and few biochemical factors are known to predict outcomes. This study evaluated whether S100A12 could be a promising marker for TAD. METHODS A total of 72 patients with DeBakey Type I TAD and 18 heart donors as control group were studied. Immunohistochemistry of TAD tissue for S100A12 and hematoxylin-eosin staining, and alizarin red staining were examined. The expression of S100A12, proinflammatory protein specific for early recruited phagocytes, was studied by Western blotting of biopsies. In addition, S100A12 was further detected in serum samples from the same groups. RESULTS S100A12 was markedly expressed in the tissue of patients with TAD in comparison with healthy control subjects (48; 66.7% vs. 0%). Serum concentrations of S100A12 in patients with TAD were significantly higher than in healthy controls (27.5 ± 2.2 vs. 16.0 ± 1.9 μg/L; P < 0.001). The upward trend of serum was consistent with that of tissue. The length of hospitalization differed significantly among S100A12 immunohistochemical groups (P < 0.001). Increased S100A12 serum levels correlated significantly with postoperative stay in hospital (r = 0.457; P < 0.001). CONCLUSIONS Our findings suggest that an elevated S100A12 level could play a crucial role in systemic inflammation and may be a promising biomarker for predicting cardiovascular events and perioperative complications in patients with TAD.

Assessing Serum Levels of ADAMTS1 and ADAMTS4 as New Biomarkers for Patients with Type A Acute Aortic Dissection

Background Type A AAD, a serious cardiovascular emergency requiring urgent surgery, is the most common and serious AAD. The aim of this study was to investigate the diagnostic value of ADAMTS1 and ADAMTS4 in patients with type A acute aortic dissection (AAD). Material/Methods Immunohistochemistry and qRT-PCR were used to evaluate the protein and mRNA expression levels of ADAMTS1 and ADAMTS4 in 14 type A acute aortic dissection (AAD) tissues and 10 control aortic tissues. Serum ADAMTS1 and ADAMTS4 expression levels in 74 patients with type A AAD, 36 patients with hypertension (HPT), and 34 healthy donors were examined by ELISA. The diagnostic value of serum ADAMTS1 and ADAMTS4 were determined by receiver operator characteristic curve (ROC). Furthermore, the dynamic change of serum ADAMTS1, ADAMTS4, D-dimer, and CRP were detected before and after surgery at different time-points in 14 patients with type A AAD. Results ADAMTS1 and ADAMTS4 protein and mRNA expression levels were found to be significantly higher in 14 type A AAD tissues (p<0.0001) compared with 10 control tissues. Serum ADAMTS1 and ADAMTS4 levels were significant higher in patients with type A AAD than those in the HPT and HD group (p<0.0001 for both). The AUC value, sensitivity, and specificity of ADAMTS1 were 0.9710 (95% CI: 0.9429 to 0.9991), 87.84%, and 97.06%, respectively, and those of ADAMTS4 were 0.9893 (95% CI: 0.9765 to 1.002), 94.59%, and 97.06%, respectively. In addition, serum ADAMTS4 level was gradually decreased with the time extension after surgery, similar to D-dimer change. Conclusions These data suggest that measurement of serum ADAMTS1 and ADAMTS4 levels could be potential diagnostic biomarkers for type A AAD, and ADAMTS4 might be a risk factor associated with type A AAD.

Simplified total aortic arch replacement with an in situ stent graft fenestration technique for acute type A aortic dissection

Objective: Total arch replacement combined with stented elephant trunk implantation in the descending aorta has successfully improved the outcomes of acute type A aortic dissection (AAAD). However, the optimal surgical strategy for the left subclavian artery (LSA) during the procedure remains a challenge. This study aimed to present our new technique of in situ stent graft fenestration to simplify the surgical procedure for suitable cases of AAAD. Methods: From August 2008 to December 2015, a total of 106 patients underwent simplified total aortic arch replacement with an in situ stent graft fenestration technique. The mean age of the patients was 50.71 ± 11.54 years (range, 24‐78 years). Both perioperative variables and postoperative follow‐up outcome of the procedure were assessed. Results: The in‐hospital mortality rate was 7.5%. The mean cardiopulmonary bypass time was 162.73 ± 68.49 minutes, cross‐clamp time was 93.13 ± 22.29 minutes, and circulatory arrest time was 23.28 ± 5.56 minutes. Transient neurologic dysfunction was observed in five patients. No permanent neurologic dysfunction was observed, and no stroke or left arm ischemia occurred. During the follow‐up period (mean, 43.4 ± 21.53 months), the survival rates of patients were 90.6%, 85.5%, and 78.8% at 1 year, 2 years, and 7 years, respectively. No stroke or left limb ischemia was observed. The LSA perfusion was well preserved in all surviving patients, and there was no endoleak or dissection around the LSA. All patients were free from reoperation. Conclusions: The in situ graft fenestration technique could simplify the procedure of LSA reconstruction during total arch replacement, provide a good surgical view for anastomosis and hemostasis, shorten the operation time, and yield satisfactory early and midterm results. It is a safe and effective alternative approach for suitable patients with AAAD. However, the long‐term results of this technique need further evaluation.

Blocking the ERK1/2 signal pathway can inhibit S100A12 induced human aortic smooth muscle cells damage: Blocking ERK1/2 protect HASMCs

Increased levels of S100A12 and activated matrix metalloproteinase 2/9 (MMP‐2/9) produced by human aortic smooth muscle cells (HASMCs) have recently implicated in the development of thoracic aortic disease. In the present study, we investigated the effect of S100A12 on HASMCs and identified the intracellular signal pathways involved by Western blot. The results were shown that up‐expression of S100A12 in HASMCs induced cell apoptosis and inhibited cell proliferation. Additionally, S100A12 significantly increased the expression of MMP‐2, MMP‐9, and VCAM‐1 in HASMCs at translational levels. Furthermore, our results also showed that S100A12 induced HASMCs damage by increased related proteins expression was mediated by the activation of ERK1/2 signal pathway, whereas p38 MAPK had no effect on those processes. Blocked the activation of ERK1/2 could decrease S100A12 induced the apoptosis and inhibited cell proliferation of HASMCs. In conclusion, these results indicated that S100A12 could increase the expression of MMP‐2, MMP‐9, and vascular cell adhesion molecule 1 (VCAM‐1) in HASMCs via activation of ERK1/2 signal pathway, which leads to injury of HASMCs. Therefore, antagonists of ERK1/2 may be useful for treating thoracic aortic dissection.

Decreased expression of P54nrb/NonO correlates with collagen deposition and fibrosis in human aortic dissection

Aortic dissection (AD) is characterized by changes in the extracellular matrix, including fibrosis with collagen production. P54nrb/NonO is known to be involved in collagen formation. In this study, we examined whether AD is associated with abnormal P54nrb/NonO expression.