Decreased low-density lipoprotein and the presence of pulmonary arterial hypertension among newly diagnosed drug-naïve patients with systemic lupus erythematosus: D-dimer as a mediator.

Pulmonary arterial hypertension (PAH) is commonly associated with systemic lupus erythematosus (SLE). The present study investigated the relationship between coagulation and changes in lipid parameters in newly-diagnosed patients with SLE in the presence of PAH and whether the coagulation parameters were mediators between lipids and PAH presence. A total of 301 subjects scheduled for new-onset drug-naïve SLE were consecutively enrolled. Baseline data for patients without PAH and with PAH were gathered and compared. Coagulation and lipid parameters were compared across patients without lipid regulating and anticoagulation medications. Multivariable logistic regression model was applied to examine potential predictors of PAH in SLE. The relationships between them were examined using Spearman's correlation analysis. The relationship between coagulation index and lipids with SLE-PAH was evaluated using mediation analysis. Female patients accounted for 88.0% of the 301 subjects, and the average age was 32 years (range, 25-45 years). A total of 40 patients (13.3%) had PAH, and the average pulmonary artery systolic pressure (sPAP) was 55.825±26.67 mmHg. Patients with PAH were older and had higher levels of fibrin/fibrinogen degradation products (FDP), D-dimer, C-reactive protein, lower levels of complement 3, complement 4 and 25-hydroxy vitamin D3 compared with the non-PAH group. Multivariable logistic regression analysis showed that age and D-dimer were independent predictor factors for PAH. Among patients without lipid regulating and anticoagulation medications, patients in the PAH group had higher levels of D-dimer and FDP, and lower low-density lipoprotein (LDL) levels compared with patients without PAH. There was also a positive relationship between sPAP and D-dimer and FDP, and a negative relationship between sPAP and total cholesterol and LDL. Mediation analysis indicated that 25.61% of the effect of low LDL on PAH presence in systemic lupus erythematosus was mediated by D-dimer. Overall, the effect of low LDL on SLE-PAH appeared to be mediated by D-dimer, which mediated 25.61% of this effect.

Interleukin-17 aggravates right ventricular remodeling via activating STAT3 under both normoxia and hypoxia.

OBJECTIVE: Proinflammatory cytokine interleukin 17 (IL-17) is involved in ventricular remodeling, mainly of the left ventricle. This study was designed to explore the role of IL-17 played in the pathogenesis of right ventricular hypertrophy (RVH), aiming to provide a novel treatment target or diagnostic biomarker options for improving the care of RVH patients. METHODS: C57BL/6 mice were maintained in 10% O2 chamber or room air for four weeks. Right ventricular hypertrophy index (RVHI), RV/body weight ratio, pulmonary arteriolar remodeling determined by percent media thickness (%MT), and the cardiomyocyte diameter of RV were evaluated. Mice were treated with exogenous recombinant mouse IL-17 (rmIL-17, 1 µg per dose twice a week) for four weeks. H9c2 cardiomyocytes were cultured and treated with IL-17 (10 ng/mL) and STAT3 inhibitor (10 ng/mL) either under normoxia (21% O2, 5% CO2, 74% N2) or under hypoxia (3% O2, 5% CO2, 92% N2). Cardiomyocyte viability was assessed by Cell counting kit 8 (CCK-8) assay. The mRNA level was detected by RT-PCR, where as the protein expression was measured by Western blot, immunohistochemistry, and immunofluorescent analyses. RESULTS: In vivo experiments showed that IL-17 did not affect the pulmonary artery under normoxia, after treatment with rmIL-17, %MT was not changed, while RVHI and the RV/body weight ratio were increased, indicating that IL-17 directly induced right ventricular hypertrophy. In a time-course study, the mice were exposed to hypoxia for 0, 1, 2, 3, 4 weeks, respectively. We found that the expression of IL-17 was gradually upregulated in RV tissue in a time-dependent manner after one week of hypoxia exposure, especially at the third and fourth week. Cardiomyocyte hypertrophy and apoptosis were observed after the exposure of the mice to hypoxia for four weeks, rmIL-17 further aggravated the hypoxia-induced cardiomyocyte hypertrophy and apoptosis. The expression of p-STAT3 in the IL-17-deficient mice was lower than in the wild-type mice. In vitro, IL-17 inhibited cardiomyocyte viability and induced cardiomyocyte apoptosis via STAT3 under both normoxic and hypoxic conditions. CONCLUSIONS: These findings support a role for IL-17 as a mediator in the pathogenesis RVH, which might be considered as a potential novel anti-inflammation therapeutic strategy or diagnostic biomarker for RVH.

Elevated Serum Level of Angiopoietin-2 as a Potential Marker for Poor Prognosis in Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is a fast-growing cancer with poor prognosis. Patients with extensive-stage SCLC are generally treated with chemotherapy. Thus, it is essential to identify a predictor of efficacy and prognosis for SCLC. Angiopoietin-2 promotes vascular remodeling and angiogenesis. Increasing evidence reveals that angiopoietin-2 is preferentially expressed in cancer cells, and elevated angiopoietin-2 expression is related to invasive and metastatic phenotypes in various cancers. However, serum angiopoietin-2 level and its prognostic potential in SCLC have not been investigated. The aim of this study was to determine the usefulness of angiopoietin-2 level as a predictor of efficacy and prognosis for SCLC. This study consisted of sixty patients with SCLC. Each patient received four cycles of cisplatin-etoposide chemotherapy, and was followed for 36 months. Serum angiopoietin-2 levels were measured by Enzyme-linked immunosorbent assays. The angiopoietin-2 levels were significantly higher in SCLC patients than those in healthy subjects (P < 0.001). The patients were divided into high-level group (32 patients, 2,923.9 ± 294.7 pg/ml) and low-level group (28 patients, 1,789.5 ± 355.1 pg/ml) according to the mean value of the angiopoietin-2 level (2,400 pg/ml). Compared with the patients in the high-level group, the patients in the low-level group showed remarkably survival advantage (P = 0.002). During chemotherapy, the patients in the low-level group showed better treatment response than the patients in the high-level group (P < 0.05). Therefore, angiopoietin-2 might be useful as a prognostic factor for SCLC and for predicting SCLC response to chemotherapy.

Inhibition of tumor angiogenesis by HMGB1 A box peptide.

High mobility group box 1 protein (HMGB1) is a highly conserved, ubiquitous non-histone nuclear protein, which participates in maintaining nucleosome structure, regulation of gene transcription, and modulating the activity of steroid hormone receptors. Substantial evidence demonstrated that HMGB1 could be secreted into the extracellular milieu, acts as a proinflammatory cytokine and mediates the downstream inflammatory responses in endotoxemia, arthritis and sepsis. Recently, several reports suggested that HMGB1 plays a key role in tumor angiogenesis through multiple mechanisms, including up-regulation of proangiogenic factors, promoting endothelial progenitor cells homing to ischemic tumor tissues and induction of endothelial cell migration and sprouting. And blockade of HMGB1 binding to the receptor for advanced glycation end products (RAGE) with anti-HMGB1 antibody, soluble RAGE or anti-RAGE neutralizing antibody has been proved to inhibit angiogenesis efficiently. Since HMGB1 A box peptide could antagonize the HMGB1 whole length protein by competitively binding to RAGE and has been considered as a HMGB1 specific antagonist, we postulate that the HMGB1 A box peptide could function as an anti-angiogenic agent to inhibit tumor angiogenesis. In our opinion, if the hypothesis proved to be practical, HMGB1 A box peptide could be widely used in clinical settings to treat malignant tumors.