Zhipeng Hu

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.

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.

Ang II enhances noradrenaline release from sympathetic nerve endings thus contributing to the up-regulation of metalloprotease-2 in aortic dissection patients' aorta wall.

Object To test the hypothesis that angiotensin II (Ang II) could enhance noradrenaline (NA) release from sympathetic nerve endings of the aorta thus contributing to the up-regulation of matrix metalloproteinase 2 (MMP-2) during the formation of aortic dissection (AD). Methods Ang II, NA, MMP-2, MMP-9 of the aorta sample obtained during operation from aortic dissection patients were detected by High Performance Liquid Chromatography and ELISA and compared with controls. Isotope labelling method was used to test the impact of exogenous Ang II and noradrenaline on the NA release and MMP-2, MMP-9 expression on Sprague Dawley (SD) rat aorta rings in vitro. Two kidneys, one clip, models were replicated for further check of that impact in SD rats in vivo. Results The concentration of Ang II, MMP-2, 9 was increased and NA concentration was decreased in aorta samples from AD patients. Exogenous Ang II enhanced while exogenous NA restrained NA release from aortic sympathetic endings. The Ang II stimulated NA release and the following MMP-2 up-regulation could be weakened by Losartan and chemical sympathectomy. Beta blocker did not influence NA release but down-regulated MMP-2. Long term in vivo experiments confirmed that Ang II could enhance NA release and up-regulate MMP-2. Conclusions AD is initiated by MMP-2 overexpression as a result of increased NA release from sympathetic nervous endings in response to Ang II. This indicates an interaction of RAS and SAS during the formation of AD.

Interleukin 22 attenuated angiotensin II induced acute lung injury through inhibiting the apoptosis of pulmonary microvascular endothelial cells

Apoptosis of pulmonary microvascular endothelial cells (PMVECs) was considered to be closely related to the pathogenesis of acute lung injury (ALI). We aim to investigate whether IL-22 plays protective roles in lung injury through inhibiting the apoptosis of PMVECs. ALI model was induced through subcutaneous infusion of angiotensin II (Ang II). Lung injury and infiltration of inflammatory cells were evaluated by determining the PaO2/FiO2, calculation of dry to weight ratio in lung, and immunohistochemisty analysis. Apoptosis of PMVECs was determined using TUNEL assay and flow cytometry, respectively. Immunofluorescence and Western blot analysis were used to determine the expression and localization of STAT3, as well as the nucleus transmission of STAT3 from cytoplasm after IL22 treatment. Pathological findings showed ALI was induced 1 week after AngII infusion. IL22 inhibited the AngII-induced ALI, attenuated the edema in lung and the infiltration of inflammatory cells. Also, it contributed to the apoptosis of PMVECs induced by AngII. Meanwhile, significant increase was noticed in the expression of STAT3, phosphorylation of Y705-STAT3, and migration from cytoplasm to the nucleus after IL-22 treatment (P < 0.05). The activation of STAT3 by IL22 showed significant attenuation after AG490 treatment. Our data indicated that IL22 showed protective effects on lung injury through inhibiting the AngII-induced PMVECs apoptosis and PMVEC barrier injury by activating the JAK2/STAT3 signaling pathway.

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.

Morbidity and Mortality of Nosocomial Infection after Cardiovascular Surgery: A Report of 1606 Cases

SummaryNosocomial infection (NI) is one of the most significant complications arising after open heart surgery, and leads to increased mortality, hospitalization time and health resource allocation. This study investigated the morbidity, mortality, and independent risk factors associated with NI following open heart surgery. We retrospectively surveyed the records of 1606 consecutive cardiovascular surgical patients to identify those that developed NI. The NI selection criteria were based on the Centers for Disease Control and Prevention (CDC) guidelines. The term NI encompasses surgical site infection (SSI), central venous catheter-related infection (CVCRI), urinary tract infection (UTI), respiratory tract infection and pneumonia (RTIP), as well as other types of infections. Of 1606 cardiovascular surgery patients, 125 developed NI (7.8%, 125/1606). The rates of NI following surgery for congenital malformation, valve replacement, and coronary artery bypass graft were 2.6% (15/587), 5.5% (26/473) and 13.6% (32/236), respectively. The NI rate following surgical repair of aortic aneurysm or dissection was 16.8% (52/310). Increased risk of NI was detected for patients with a prior preoperative stay ≥3 days (OR=2.11, 95% CI=1.39–3.20), diabetes (OR=2.00, 95%=CI 1.26–3.20), length of surgery ≥6 h (OR=2.26, 95% CI=1.47–3.47), or postoperative cerebrovascular accident (OR=4.08, 95% CI=1.79–9.29). Greater attention should be paid toward compliance with ventilator and catheter regulations in order to decrease NI morbidity and mortality following cardiovascular procedures.

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.

JAK2/STAT3 Pathway Was Associated with the Protective Effects of IL-22 On Aortic Dissection with Acute Lung Injury

Patients with aortic dissection (AD) may present acute lung injury (ALI) that may affect the prognosis. In this study, we aim to investigate the roles and mechanism of IL-22 in the pathogenesis of AD complicated with ALI. Six hundred and twenty-one AD patients were included, and the incidence of ALI and pulmonary CT findings were analyzed. Mouse ALI model was established through AngII, and then IL-22 injection and AG490 were given. The pathological changes, infiltration of inflammatory cells, and expression of STAT3 were determined. For the in vitro experiment, cultivated pulmonary microvascular endothelial cells (PMVECs) were treated by angiotensin II (AngII), followed by treating with IL-22 and/or AG490. The expression and migration of STAT3 was determined. Flow cytometry was carried out to evaluate the apoptosis. IL-22 contributed to the expression of STAT3 in lung tissues and attenuation of ALI. IL-22 obviously inhibited the apoptosis of PMVECs mediated by AngII and downregulated the expression and intranuclear transmission of STAT3. Such phenomenon was completely inhibited upon administration of AG490, an inhibitor of JAK2. Our data showed IL-22 contributed to the inhibition of PMVEC apoptosis mediated by AngII through activating the JAK2/STAT3 signaling pathway, which may attenuate the ALI induced by AngII.

Association between blood vitamin D and myocardial infarction: A meta-analysis including observational studies

BACKGROUND The association between blood vitamin D levels and the risk of myocardial infarction (MI) is controversial. This meta-analysis aimed to describe the relationship between MI risk and blood vitamin D levels. METHODS Online databases were searched in PubMed, EMBASE and Web of science till February 2017 for observational studies in relation to reporting the vitamin D levels in MI cases and non-MI controls. The weighted mean difference (WMD) or odds ratio (OR), with 95% confidence interval (CI), were calculated to evaluate the relationship between MI risk and blood vitamin D levels. RESULTS Eight observational studies with 9913 individuals, consisted of 3411 MI patients and 6502 non-MI controls, were included in our study. The pooled results revealed that blood vitamin D levels were significantly lower in MI patients when compared with non-MI controls (WMD=-3.40; 95% CI: -5.87 to -0.92, P=0.007). Subgroup analyses indicated MI patients were also associated with lower levels of blood vitamin D in America and Asia. Furthermore, when compared to non-MI controls, sufficient blood vitamin D appeared to protect against the occurrence of MI (OR=0.44; 95% CI: 0.25 to 0.76, P=0.004) in MI patients. Subgroup analyses also showed that sufficient blood 25(OH)D levels was a protective factor for MI in America and Asia. CONCLUSIONS Present study suggested that the levels of blood 25(OH)D were significant lower in MI patients, especially in America and Asia, and sufficient blood vitamin D levels might protect against the occurrence of MI.

Palmitoylethanolamide (PEA): A promising biomarker for coronary dysfunction in MOB individuals

Article history: Received 27 February 2017 Received in revised form 11 March 2017 Accepted 26 April 2017 ed. Secondly, the evidence of PEA associated with disease severity was unwarranted. Finally, the cost-effectiveness of PEA as a new biomarker also needs further investigations. In conclusion, a significant amount of work is required to apply PEA as a new biomarker to predict coronary dysfunction in clinical practice.