Description: Rationale: Intimal calcification is highly correlated with atherosclerotic plaque burden, but the underlying mechanism is poorly understood. We recently reported that cartilage oligomeric matrix protein (COMP), a component of vascular extracellular matrix, is an endogenous inhibitor of vascular smooth muscle cell calcification. Objective: To investigate whether COMP affects atherosclerotic calcification. Methods and Results: ApoE –/– COMP –/– mice fed with chow diet for 12 months manifested more extensive atherosclerotic calcification in the innominate arteries than did ApoE –/– mice. To investigate which origins of COMP contributed to atherosclerotic calcification, bone marrow transplantation was performed between ApoE –/– and ApoE –/– COMP –/– mice. Enhanced calcification was observed in mice transplanted with ApoE –/– COMP –/– bone marrow compared with mice transplanted with ApoE –/– bone marrow, indicating that bone marrow–derived COMP may play a critical role in atherosclerotic calcification. Furthermore, microarray profiling of wild-type and COMP –/– macrophages revealed that COMP-deficient macrophages exerted atherogenic and osteogenic characters. Integrin β3 protein was attenuated in COMP –/– macrophages, and overexpression of integrin β3 inhibited the shift of macrophage phenotypes by COMP deficiency. Furthermore, adeno-associated virus 2–integrin β3 infection attenuated atherosclerotic calcification in ApoE –/– COMP –/– mice. Mechanistically, COMP bound directly to β-tail domain of integrin β3 via its C-terminus, and blocking of the COMP–integrin β3 association by β-tail domain mimicked the COMP deficiency–induced shift in macrophage phenotypes. Similar to COMP deficiency in mice, transduction of adeno-associated virus 2–β-tail domain enhanced atherosclerotic calcification in ApoE –/– mice. Conclusions: These results reveal that COMP deficiency acted via integrin β3 to drive macrophages toward the atherogenic and osteogenic phenotype and thereby aggravate atherosclerotic calcification.

Description: Introduction There have been inconsistent findings from randomised controlled trials (RCTs) and systematic reviews on the efficacies of selective serotonin reuptake inhibitors (SSRIs) as the first-line treatment of major depressive disorder (MDD). Besides inconsistencies among randomised controlled trials (RCTs), their risks of bias and evidence grading have seldom been evaluated in meta-analysis. This study aims to compare the efficacy of SSRIs by conducting a Bayesian network meta-analysis, which will be the most comprehensive evaluation of evidence to resolve the inconsistency among previous studies. Methods and analyses SSRIs including citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline and vilazodone have been selected. Systematic database searching and screening will be conducted for the RCTs on drug treatment of patients with MDD according to pre-specified search strategies and selection criteria. PubMed, the Cochrane Library, EMBASE, ScienceDirect, the US Food and Drug Administration Website, ClinicalTrial.gov and WHO Clinical Trials will be searched. Outcome data including Hamilton Depression Rating Scale (HDRS), Montgomery-Åsberg Depression Rating Scale (MADRS) and Clinical Global Impression (CGI) from eligible RCTs will be extracted. The outcomes will be analysed as ORs and mean differences under a random-effects model. A Bayesian network meta-analysis will be conducted with WinBUGS software, to compare the efficacies of SSRIs. Subgroup and sensitivity analysis will be performed to explain the study heterogeneity and evaluate the robustness of the results. Meta-regression analysis will be conducted to determine the possible factors affecting the efficacy outcomes. The Cochrane risk of bias assessment tool will be used to assess the RCT quality, and the Grading of Recommendation, Assessment, Development and Evaluation will be used to assess the strength of evidence from the meta-analysis. Ethics and dissemination No ethical approval is required because this study includes neither confidential personal patient data nor interventions with patients. Protocol registration number CRD42015024879.