Epigenetic Regulation of Vascular Smooth Muscle Cells by Histone H3 Lysine 9 Dimethylation Attenuates Target Gene-Induction by Inflammatory Signaling.

OBJECTIVE: Vascular inflammation underlies cardiovascular disease. Vascular smooth muscle cells (VSMCs) upregulate selective genes, including MMPs (matrix metalloproteinases) and proinflammatory cytokines upon local inflammation, which directly contribute to vascular disease and adverse clinical outcome. Identification of factors controlling VSMC responses to inflammation is therefore of considerable therapeutic importance. Here, we determine the role of Histone H3 lysine 9 di-methylation (H3K9me2), a repressive epigenetic mark that is reduced in atherosclerotic lesions, in regulating the VSMC inflammatory response. Approach and Results: We used VSMC-lineage tracing to reveal reduced H3K9me2 levels in VSMCs of arteries after injury and in atherosclerotic lesions compared with control vessels. Intriguingly, chromatin immunoprecipitation showed H3K9me2 enrichment at a subset of inflammation-responsive gene promoters, including MMP3, MMP9, MMP12, and IL6, in mouse and human VSMCs. Inhibition of G9A/GLP (G9A-like protein), the primary enzymes responsible for H3K9me2, significantly potentiated inflammation-induced gene induction in vitro and in vivo without altering NFκB (nuclear factor kappa-light-chain-enhancer of activated B cell) and MAPK (mitogen-activated protein kinase) signaling. Rather, reduced G9A/GLP activity enhanced inflammation-induced binding of transcription factors NFκB-p65 and cJUN to H3K9me2 target gene promoters MMP3 and IL6. Taken together, these results suggest that promoter-associated H3K9me2 directly attenuates the induction of target genes in response to inflammation in human VSMCs. CONCLUSIONS: This study implicates H3K9me2 in regulating the proinflammatory VSMC phenotype. Our findings suggest that reduced H3K9me2 in disease enhance binding of NFκB and AP-1 (activator protein-1) transcription factors at specific inflammation-responsive genes to augment proinflammatory stimuli in VSMC. Therefore, H3K9me2-regulation could be targeted clinically to limit expression of MMPs and IL6, which are induced in vascular disease.

Bouveret Syndrome: A Systematic Review of Endoscopic Therapy and a Novel Predictive Tool to Aid in Management.

BACKGROUND AND GOALS: Bouveret syndrome is characterized by gastroduodenal obstruction caused by an impacted gallstone. Current literature recommends endoscopic therapy as the first line of intervention despite significantly lower success rates compared with surgery. The lack of treatment efficacy studies and the paucity of clinical guidelines contribute to current practices being arbitrary. The aim of this systematic review was to identify factors that predict outcomes of endoscopic therapy. Subsequently, a predictive tool was devised to predict the success of endoscopic therapy and recommendations were proposed to improve current management strategies of impacted gallstones in the upper gastrointestinal tract. METHODS: A systematic search of PubMed, Medline, Cochrane, and Scopus was performed for articles that contained the terms "Bouveret syndrome," "Bouveret's syndrome," "gallstone" AND "gastric obstruction" and "gallstone" AND "duodenal obstruction" that were published between January 1, 1950 to April 15, 2018. Articles were reviewed by 3 reviewers and raw data collated. χ and Kolmogorov-Smirnov tests were used to test associations between predictors and endoscopic outcomes. A logistic regression model was then used to create a predictive tool which was cross validated. RESULTS: Failure of endoscopic therapy is associated with increasing gallstone length (P<0.0001) and impaction in the distal duodenum (P<0.05). Using multiple endoscopic modalities is associated with better success rates (P<0.05). The novel predictive tool predicted success of endoscopic therapy with an area under the receiver operating characteristic score of 0.86 (95% confidence interval: 0.79-0.94). CONCLUSION: In Bouveret syndrome, a selective approach to endoscopic therapy can expedite definitive treatment and improve current management strategies.