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The histone deacetylase inhibitor valproic acid (VPA) pleotropiclly modulates cytokine and hypoxia‐dependent dysregulation of genes that predispose the formation of intraabdominal adhesions in cultured human mesothelial cells (HMCs)
Author(s) -
Gruver Charles,
Heydrick Stanley,
Stucchi Arthur F
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.717.3
Subject(s) - fibrinolysis , endocrinology , medicine , thrombomodulin , fibrin , tissue factor pathway inhibitor , chemistry , thrombin , tissue factor , immunology , platelet , coagulation
Mesothelial injury initiates the secretion of a fibrinous exudate, the formation of a fibrin matrix and the formation of abdominal adhesions. Inflammation suppresses peritoneal fibrinolysis and mitigating this decrease reduces adhesions. We showed that VPA inhibits adhesions by a mechanism independent of peritoneal fibrinolysis. Our objective was to examine the mechanism(s) by which VPA counters the dysregulation of key adhesiogenic genes. Cultured HMCs were treated with either the cytokines TGFβ+IL1β+IFNγ (C), the hypoxia mimetic dimethyloxaloglycine (D) or both, +/− 2 mM VPA, and mRNA levels for vascular endothelial growth factor (VEGF; vascular extravasation), thrombomodulin (TM; inhibits thrombin), and tissue plasminogen activator (tPA); activates plasmin) were measured at 6 hrs via RT‐PCR. VPA 1) blunted the increase of VEGF mRNA by D (7.4±1.4 vs 4.0±0.5 fold over control) and D+C (23.9 ±9 vs 10.1±1.5 fold over control, both p<.01); 2) increased TM mRNA 2‐fold in all groups (p<.05 for all), inhibiting thrombin activation; and 3) induced tPA mRNA to increase in response to C (1.4±0.3 vs 4.3±1.2 fold over control) and D+C (1.1±0.4 to 2.7±10.6 fold over control, both p<.05). VPA may decrease fibrinogen levels in the peritoneum, its conversion to fibrin, and blunt the decrease in fibrinolytic activity. Funded by Cooper‐Tyler Endowment, Department of Surgery, Boston University Medical Center.