RESUMEN
Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, is a widely used anticonvulsant drug that is currently undergoing clinical evaluation for anticancer therapy due to its anti-angiogenic potential. Endothelial cells (ECs) can transition into mesenchymal cells and this form of EC plasticity is called endothelial-to-mesenchymal transition (EndMT), which is widely implicated in several pathologies including cancer and organ fibrosis. However, the effect of VPA on EC plasticity and EndMT remains completely unknown. We report herein that VPA-treatment significantly inhibits tube formation, migration, nitric oxide production, proliferation and migration in ECs. A microscopic evaluation revealed, and qPCR, immunofluorescence and immunoblotting data confirmed EndMT-like phenotypic switching as well as an increased expression of pro-fibrotic genes in VPA-treated ECs. Furthermore, our data confirmed important and regulatory role played by TGFß-signaling in VPA-induced EndMT. Our qPCR array data performed for 84 endothelial genes further supported our findings and demonstrated 28 significantly and differentially regulated genes mainly implicated in angiogenesis, endothelial function, EndMT and fibrosis. We, for the first time report that VPA-treatment associated EndMT contributes to the VPA-associated loss of endothelial function. Our data also suggest that VPA based therapeutics may exacerbate endothelial dysfunction and EndMT-related phenotype in patients undergoing anticonvulsant or anticancer therapy, warranting further investigation.
RESUMEN
OBJECTIVES: This meta-analysis compares total arterial revascularization (TAR) versus conventional coronary artery bypass and additionally to two arterial grafts. METHODS: We searched MEDLINE and EMBASE Databases from 1996-to-2016 for studies comparing TAR versus non-TAR for multi-vessel surgical revascularization. Data were extracted by 2 independent investigators. Meta-analysis used random effects, which incorporates heterogeneity. RESULTS: There were 4 smaller shorter follow-up randomized controlled trials (RCTs), plus 15 matched/adjusted and 6 unmatched/unadjusted larger longer follow-up observational studies that met inclusion criteria (N=130.305 patients; mean follow-up range: 1-15years). There were no differences in perioperative stroke, myocardial infarction or mortality. However, TAR was associated with lower long term all-cause mortality in observational studies matched/adjusted for confounders (incident rate ratio 0.85, 95% CI: 0.81-0.89, p<0.0001; I2=0%) and unmatched/unadjusted (incident rate ratio 0.67, 95% CI: 0.59-0.76, p<0.0001; I2=67%) for TAR. Decreases in major cardiovascular outcomes and revascularization did not achieve statistical significance. There were greater sternal complications with TAR in the matched/adjusted studies (pooled risk ratio 1.21, 95% CI: 1.03-1.42, p=0.02; I2=0%). When compared to patients with two arterial grafts, TAR was still associated with reduced long-term all-cause mortality (incident rate ratio 0.85, 95% CI: 0.73-0.99, p=0.04) with minimal heterogeneity (I2=5%). CONCLUSIONS: Data from primarily observational studies suggest that TAR may improve long-term survival compared with conventional coronary bypass by 15-20% even when compared with two arterial grafts. Prospective randomized trials of TAR with long term follow-up are needed.