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Coronary restenosis is an important cause of poor long-term prognosis in patients with coronary heart disease. Here, we show that lysine methyltransferase SMYD2 expression in the nucleus is significantly elevated in serum- and PDGF-BB-induced vascular smooth muscle cells (VSMCs), and in tissues of carotid artery injury-induced neointimal hyperplasia. Smyd2 overexpression in VSMCs (Smyd2-vTg) facilitates, but treatment with its specific inhibitor LLY-507 or SMYD2 knockdown significantly inhibits VSMC phenotypic switching and carotid artery injury-induced neointima formation in mice. Transcriptome sequencing revealed that SMYD2 knockdown represses the expression of serum response factor (SRF) target genes and that SRF overexpression largely reverses the inhibitory effect of SMYD2 knockdown on VSMC proliferation. HDAC3 directly interacts with and deacetylates SRF, which enhances SRF transcriptional activity in VSMCs. Moreover, SMYD2 promotes HDAC3 expression via tri-methylation of H3K36 at its promoter. RGFP966, a specific inhibitor of HDAC3, not only counteracts the pro-proliferation effect of SMYD2 overexpression on VSMCs, but also inhibits carotid artery injury-induced neointima formation in mice. HDAC3 partially abolishes the inhibitory effect of SMYD2 knockdown on VSMC proliferation in a deacetylase activity-dependent manner. Our results reveal that the SMYD2-HDAC3-SRF axis constitutes a novel and critical epigenetic mechanism that regulates VSMC phenotypic switching and neointimal hyperplasia.
RESUMO
Background: Majority of poorly functioning kidney (PFK) due to primary ureteropelvic junction obstructions (UPJO) in young adult have potential to recover after an attempted percutaneous nephrostomy (PCN). The split renal function measured by nuclear renal scan may not be sufficient enough to predict recovery of such kidney. Therefore, this study was undertaken to determine the functional recovery and potential salvageability of PFK due UPJO. Objective of the study was to evaluate safety and efficacy of PCN in adult patients with severe hydronephrosis due to PUJO.Methods: A total of 25 (10 male and 15 female) young adult patients of severe hydronephrosis due to PUJO and SRF<20% underwent PCN procedures. Only, those who had significant improvement in their SRF ≥10% and developed PCN output ≥400 ml/day underwent Anderson-Hyenas pyeloplasty and rest underwent nephrectomy.Results: Both male and female young patients had significantly improvement after 6 weeks of PCN, their mean pre-PCN SRF changed from 16.30% and 12.27% to became 28.10±08.41% and 18.53±09.89%, respectively. Those with age <30 years improved most with ≥10% increase in the mean SRF and in 72% patients average PCN output increased from 279.80±93.90 ml/day to 445.20±160.341 ml/day at 6 weeks period. Overall, the patients with average PCN output ≥400 ml/day had a mean improvement of 10.33±05.48% in SRF. However, 5(20%) developed haematuria, 8% fever, 16% displaced PCN tip with no major puncture site bleed.Conclusions: The trial of PCN before definite surgery in young adult patients with poorly functioning kidney due to UPJO not only predicts renal renal function recovery but also prevent unwarranted renal loss.
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Objective_To study the effect of Y-27632 on invasion and motility of SGC-7901 gastric carcinoma cells, and to find whether Y-27632 excerts the effect by attenuating SRF expression.Methods_SGC-7901 gastric carcinoma cells were divided into 3 groups:1)blank control group;2)Y-27632 group;3)siRNA-SRF-1107 group. Transfected siRNA-SRF or incubated by Y-27632 48 h.The effect of Y-27632 on proliferation suppressions of SGC-7901 gastric carcinoma cells was detected by CCK-8 assay.Cell invasion was examined by Transwell and wound healing test.The expression of SRF, ROCK1, E-cadherin, β-catenin, F-actin, MRTF-A and Cyclin D1 were detected by Western blot.Results_Y-27632 inhibited invasion (P<0.05)but had no effect on proliferation of SGC-7901 gastric carcinoma cells.Y-27632 reduced ROCK1, MRTF-A, F-actin, SRF protein expressions by 37.0%, 44.3%, 62.7%and 62.7%respectively, and E-cadherin protein expression was up-regulated by 2.64 folds(P<0.05).Conclusions_The inhibition of ROCK and up-regulation of E-cadherin by Y-27632 can inhibit the invasion and migration of SGC-7901 gastric carcinoma cells that is explained at least, in part, by attenuating SRF expression.