MicroRNA-766-3p Contributes to Anti-Inflammatory Responses through the Indirect Inhibition of NF-κB Signaling.

MicroRNA (miRNA) is small RNA of 20 to 22 nucleotides in length and is stably present in plasma. Regulating the expression of miRNA taken into cells has been suggested as a general therapeutic approach. We identified the novel anti-inflammatory miRNA hsa-miR-766-3p and investigated its biological function in human rheumatoid arthritis (RA) fibroblast-like synoviocyte MH7A cells. To verify the function of the miRNA present in the plasma of RA patients, we performed a comprehensive analysis of the miRNA expression during abatacept treatment and identified eight miRNAs with significantly altered expression levels. Among these eight miRNAs, miR-766-3p was found to have a clear function. The expression of inflammatory genes in response to inflammatory stimuli was suppressed in MH7A transduced with miR-766-3p. We showed that miR-766-3p indirectly reduced the activation of NF-κB and clarified that this mechanism was partially involved in the reduction of the mineralocorticoid receptor expression. In addition, the inflammatory responses were suppressed in other types of cells. These results indicate the novel function of miR-766-3p, findings that may aid in the development of therapies to suppress inflammation, not only in RA but also in other diseases.

Kinase inhibitors of the IGF-1R as a potential therapeutic agent for rheumatoid arthritis.

We have previously shown that the inhibition of connective tissue growth factor (CTGF) is a potential therapeutic strategy against rheumatoid arthritis (RA). CTGF consists of four distinct modules, including the insulin-like growth factor binding protein (IGFBP). In serum, insulin-like growth factors (IGFs) bind IGFBPs, interact with the IGF-1 receptor (IGF-1 R), and regulate anabolic effects and bone metabolism. We investigated the correlation between IGF-1 and the pathogenesis of RA, and the inhibitory effect on osteoclastogenesis and angiogenesis of the small molecular weight kinase inhibitor of the IGF-1 R, NVP-AEW541, against pathogenesis of RA in vitro. Cell proliferation was evaluated by cell count and immunoblotting. The expression of IGF-1 and IGF-1 R was evaluated by RT-PCR. Osteoclastogenesis was evaluated using tartrate-resistant acid phosphatase staining, a bone resorption assay, and osteoclast-specific enzyme production. Angiogenesis was evaluated by a tube formation assay using human umbilical vein endothelial cells (HUVECs). The proliferation of MH7A cells was found to be inhibited in the presence of NVP-AEW541, and the phosphorylation of extracellular signal-regulated kinase (ERK) and Akt was downregulated in MH7A cells. IGF-1 and IGF-1 R mRNA expression levels were upregulated during formation of M-colony stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL)-mediated osteoclast formation. Moreover, osteoclastogenesis was suppressed in the presence of NVP-AEW541. The formation of the tubular network was enhanced by IGF-1, and this effect was neutralized by NVP-ARE541. Our findings suggest that NVP-AEW541 may be utilized as a potential therapeutic agent in the treatment of RA.

Identifying Small Coronary Calcification in Non-Contrast 0.5-mm Slice Reconstruction to Diagnose Coronary Artery Disease in Patients with a Conventional Zero Coronary Artery Calcium Score.

AIMS: In a new-generation computed tomography (CT) scanner, coronary artery calcium (CAC) scores were measured using 3.0-mm slice reconstruction images originally acquired with 0.5 mm thickness scans in a single beat. This study investigated the usefulness of thin-slice (0.5 mm) reconstruction for identifying small calcifications in coronary arteries and evaluated the association with coronary plaques and stenosis compared to conventional 3.0-mm reconstruction images. METHODS: We evaluated 132 patients with zero CAC scores in conventional 3.0-mm Agatston method using a 320-slice CT. Then, 0.5-mm slice reconstruction was performed to identify small calcifications. The presence of stenosis and coronary plaques was assessed using coronary CT angiography. RESULTS: In total, 22 small calcifications were identified in 18 patients. There were 28 (21%) patients with any (≥ 25%) stenosis (34 lesions). Forty-seven coronary plaques were found in 33 patients (25%), including 7 calcified plaques in 7 patients (5%), 34 noncalcified plaques in 27 patients (20%), and 6 partially calcified plaques in 5 patients (4%). Patients with small calcifications had a significantly higher prevalence of noncalcified or partially calcified plaques (83% vs 14%; p＜0.001) and obstructive stenosis (33% vs 5.2%; p＜0.001) compared to those without small calcifications. The addition of small calcifications to the coronary risk factors when diagnosing stenosis significantly improved the diagnostic value. CONCLUSION: Small calcifications detected by thin-slice 0.5-mm reconstruction are useful for distinguishing coronary atherosclerotic lesions in patients with zero CAC scores from conventional CT reconstruction.

Data set for volumetric and pathological findings of epicardial adipose tissue.

This article contains the data regarding clinically-assessed visceral adipose tissue (VAT) area and epicardial adipose tissue (EAT) volume on computed tomography (CT) images and EAT pathology, represented by inflammation and neoangiogenesis, complementing the data reported by Kitagawa et al. [1]. In 45 patients scheduled for cardiac surgery, we studied CT images obtained prior to surgery and the numbers of CD68+ individual macrophages and CD31+ neovessels in EAT samples subsequently obtained during surgery. The data revealed a moderate correlation between VAT area and EAT volume, and a strong correlation between EAT macrophage infiltration and neoangiogenesis.

The relationship between inflammation and neoangiogenesis of epicardial adipose tissue and coronary atherosclerosis based on computed tomography analysis.

OBJECTIVE: Previous studies indicate that epicardial adipose tissue (EAT) biologically contributes to the progression of coronary atherosclerosis. We evaluated the relationship between EAT pathology, represented by inflammation and neoangiogenesis, and coronary atherosclerosis on computed tomography (CT) images. METHODS: We performed CT examination in 45 patients scheduled for cardiac surgery (coronary artery bypass graft [CABG], n = 21; non-CABG, n = 24) to assess visceral adipose tissue (VAT) area, EAT volume, coronary calcium score (CCS), and presence of non-calcified coronary plaque (NCP) on CT angiography. Each patient was assessed with the numbers of CD68(+) individual macrophages and CD31(+) neovessels in six random high-power fields (400×) of EAT samples subsequently obtained during cardiac surgery. RESULTS: In three groups based on CCS (mild, 0-100; moderate, 101-400; severe, >400), the moderate group had the most extensive macrophage infiltration (p = 0.0025) and neoangiogenesis (p = 0.0036) in EAT. The patients with NCP had more extensive macrophage infiltration (p = 0.010) and neoangiogenesis (p = 0.0043) in EAT than those without. On multivariate analysis adjusted for age, sex, CABG versus. non-CABG, VAT area, and EAT volume, moderate CCS and the presence of NCP showed significant correlations with increased macrophage infiltration (ß = 0.65; p < 0.0001, and ß = 0.49; p = 0.0089, respectively) and neoangiogenesis (ß = 0.55; p = 0.0011, and ß = 0.53; p = 0.012, respectively) in EAT. CONCLUSION: Inflammation and neoangiogenesis in EAT independently correlate with moderate coronary calcification and presence of NCP, suggesting that these two factors may have a role in promoting coronary atherosclerosis.

Incremental prognostic value of cardiac computed tomography angiography in asymptomatic aortic stenosis: significance of aortic valve calcium score.

BACKGROUND: Cardiac computed tomography angiography (CCTA) provides the simultaneous evaluation of the aortic valve, myocardium, and coronary arteries. In particular, aortic valve calcium score (AVCS) can be accurately measured on the same scanning sequence used to measure coronary artery calcification, with no additional cost or radiation exposure. We sought to evaluate the prognostic value of CCTA measures, including AVCS, in asymptomatic aortic stenosis (AS). METHODS AND RESULTS: Sixty-four initially asymptomatic patients with AS with a normal ejection fraction were prospectively enrolled and followed for median 29 (IQR=18-50) months. During follow-up, 27 (42%) patients experienced cardiac events, including five cardiac deaths, eleven aortic valve replacements. Multivariate Cox proportional hazards analysis identified three CCTA measures as significant predictors of cardiac events: aortic valve area (per 0.1cm(2) decrease; hazard ratio [HR]: 1.19, 95% confidence interval [CI]: 1.05-1.34); multi-vessel obstructive coronary artery disease (HR: 2.84, 95% CI: 1.10-7.32); and AVCS (per 100; HR: 1.09, 95% CI: 1.04-1.15). Kaplan-Meier analysis showed that patients with AVCS greater than or equal to the median value of 723 had significantly worse outcomes than those with AVCS less than 723 (p<0.0001). The C-statistic value for cardiac events substantially increased when these CCTA measures were added to clinical characteristics plus echocardiographic peak transaortic velocity (0.913 vs. 0.702, p<0.001). CONCLUSIONS: In patients with asymptomatic AS, CCTA measures of valve area, coronary stenosis, and calcification severity provide independent and incremental prognostic value after accounting for the echocardiographic severity of stenosis.