No abstract

Coronary in-stent restenosis is a late complication of angioplasty. It is a multifactorial process that involves vascular smooth muscle cells (VSMCs), endothelial cells, and inflammatory and genetic factors. In this study, the transcriptomic landscape of VSMCs’ phenotypic switch process was assessed under stimuli resembling stent injury. Co-cultured contractile VSMCs and endothelial cells were exposed to a bare metal stent and platelet-derived growth factor (PDGF-BB) 20 ng/mL. Migratory capacity (wound healing assay), proliferative capacity, and cell cycle analysis of the VSMCs were performed. RNAseq analysis of contractile vs. proliferative VSMCs was performed. Gene differential expression (DE), identification of new long non-coding RNA candidates (lncRNAs), gene ontology (GO), and pathway enrichment (KEGG) were analyzed. A competing endogenous RNA network was constructed, and significant lncRNA–miRNA–mRNA axes were selected. VSMCs exposed to “stent injury” conditions showed morphologic changes, with proliferative and migratory capacities progressing from G0-G1 cell cycle phase to S and G2-M. RNAseq analysis showed DE of 1099, 509 and 64 differentially expressed mRNAs, lncRNAs, and miRNAs, respectively. GO analysis of DE genes showed significant enrichment in collagen and extracellular matrix organization, regulation of smooth muscle cell proliferation, and collagen biosynthetic process. The main upregulated nodes in the lncRNA-mediated ceRNA network were PVT1 and HIF1-AS2, with downregulation of ACTA2-AS1 and MIR663AHG. The PVT1 ceRNA axis appears to be an attractive target for in-stent restenosis diagnosis and treatment.

Statins are the first-line therapy prescribed to lower plasma cholesterol levels. Although being safe and showing several beneficial cholesterol-independent pleiotropic effects, a significant variability regarding statin's therapeutic goals has been abundantly documented, but less understood. We aimed to investigate the influence of the ABCC2 -24C>T single nucleotide polymorphism on Chilean hypercholesterolaemic individuals treated for 4 weeks with 10 mg/day atorvastatin. A total of 127 individuals medicated with atorvastatin 10 mg/day/4 weeks were included. Lipid profiles were determined before and after drug administration by conventional assays. Genotyping of the ABCC2 rs717620 SNP (-24C>T) was performed with TaqMan Drug Metabolism Genotyping Assays. As expected, atorvastatin reduced TC, LDL-C and TG concentrations (p < 0.05). Also, HDL-C levels were increased (p < 0.05). Minor allele frequency for the rs717620 was 0.232. Overall, atorvastatin response was not associated with the ABCC2 rs717620 SNP (p > 0.05). Nonetheless, in male individuals carrying the -24T allele, we observed an attenuated reduction in both TG values and the TG/HDL-C ratio after 10 mg/day atorvastatin. This study indicates that TG levels and the TG/HDL-C ratio are affected by the rs717620 SNP in Chilean males but not female individuals after atorvastatin treatment.

Background After the appearance of new biologics are more treatment options for first and second-line individualising according to the characteristics of each patient. The efficacy of a second anti-TNF is lower than the initial treatment so a more efficient strategy could change the therapeutic target. Methods We included patients with an established diagnosis of Crohn’s disease who were on second-line biological treatment (ustekinumab or anti-TNF) after failure of a first anti-TNF (adalimumab or infliximab) treatment. Only patients in whom the indication was the ‘induction of remission of inflammatory activity’ so those patients in whom the indication was different from the intestinal activity (intestinal manifestations, perianal disease etc.) were selected were not considered valid for analysis. Patients who had undergone intestinal resection alone were included in the study if the indication of second-line biologic treatment was already established and no recurrence prophylaxis thereof. Results A total of 56 patients with an established diagnosis of Crohn’s disease stable tracking unit EII La Paz Hospital who were treated with second-line ustekinumab (21 patients, 37.5%) or anti-TNF (35 patients were included, 62.5%) for remission induction. Baseline characteristics of patients and their IBD are summarised in Table 1. The duration of biological treatment at the time of analysis was 1.48 years (SD: 1.2) for ustekinumab group and 3.55 years (SD 3.3) for the anti-TNF group. Ustekinumab group in 16/21 (76.2%) achieved clinical remission, 3/21 (14.3%) had no response while achieving remission (note that in one patient occurred exitus otherwise cause adenocarcinoma páncreas- unable to properly assess drug response), 2/21 patients (9.5%) did not answer. In the group of anti-TNF, 15/35 patients (42.8%) achieved clinical remission, 12/35 patients (34.3%) had response without remission, 8/35 patients (22.9%) No response. These differences between groups reached statistical significance (p = 0.015). Among patients who achieved a response / clinical remission included those wherein assessed by endoscopy identifying intestinal activity no statistically significant differences between groups vs. anti-TNF ustekinumab both SESCD (average 2 vs. 6.3 p = 0, 39) to the Ruttgerts in (mean 2.5 vs. 2, p = 0.67) postsurgical stage. Regarding the response/biological remission found no significant differences in CRP between ustekinumab and anti-TNF (4.55 vs. 5.79, p = 0.68) or with fecal calprotectin (276.25 vs. 268.82, p = 0.94). Conclusion In our experience, the second-line treatment with ustekinumab after the failure of a first anti-TNF has better remission rates and response to treatment with a second anti-TNF.

Circulating endothelial progenitor cells (EPCs) play an important role in the repair processes of damaged vessels, favoring re-endothelization of stented vessels to minimize restenosis. EPCs number and function is diminished in patients with type 2 diabetes, a known risk factor for restenosis. Considering the impact of EPCs in vascular injury repair, we conducted a meta-analysis of microarray to assess the transcriptomic profile and determine target genes during the differentiation process of EPCs into mature ECs. Five microarray datasets, including 13 EPC and 12 EC samples were analyzed, using the online tool ExpressAnalyst. Differentially expressed genes (DEGs) analysis was done by Limma method, with an | log2FC| &gt; 1 and FDR &lt; 0.05. Combined p-value by Fisher exact method was computed for the intersection of datasets. There were 3,267 DEGs, 1,539 up-regulated and 1,728 down-regulated in EPCs, with 407 common DEGs in at least four datasets. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed enrichment for terms related to “AGE-RAGE signaling pathway in diabetic complications.” Intersection of common DEGs, KEGG pathways genes and genes in protein-protein interaction network (PPI) identified four key genes, two up-regulated (IL1B and STAT5A) and two down-regulated (IL6 and MAPK11). MicroRNA enrichment analysis of common DEGs depicted five hub microRNA targeting 175 DEGs, including STAT5A, IL6 and MAPK11, with hsa-miR-124 as common regulator. This group of genes and microRNAs could serve as biomarkers of EPCs differentiation during coronary stenting as well as potential therapeutic targets to improve stent re-endothelization, especially in diabetic patients.