title: Valproic Acid Limits Pancreatic Recovery after Pancreatitis by Inhibiting Histone Deacetylases and Preventing Acinar Redifferentiation Programs.
abstract: The mechanisms by which drugs induce pancreatitis are unknown. A definite cause of pancreatitis is due to the antiepileptic drug valproic acid (VPA). On the basis of three crucial observations-that VPA inhibits histone deacetylases (HDACs), HDACs mediate pancreas development, and aspects of pancreas development are recapitulated during recovery of the pancreas after injury-we hypothesized that VPA does not cause injury on its own, but it predisposes patients to pancreatitis by inhibiting HDACs and provoking an imbalance in pancreatic recovery. In an experimental model of pancreatic injury, we found that VPA delayed recovery of the pancreas and reduced acinar cell proliferation. In addition, pancreatic expression of class I HDACs (which are the primary VPA targets) increased in the midphase of pancreatic recovery. VPA administration inhibited pancreatic HDAC activity and led to the persistence of acinar-to-ductal metaplastic complexes, with prolonged Sox9 expression and sustained β-catenin nuclear activation, findings that characterize a delay in regenerative reprogramming. These effects were not observed with valpromide, an analog of VPA that lacks HDAC inhibition. This is the first report, to our knowledge, that VPA shifts the balance toward pancreatic injury and pancreatitis through HDAC inhibition. The work also identifies a new paradigm for therapies that could exploit epigenetic reprogramming to enhance pancreatic recovery and disorders of pancreatic injury.
authors.affiliation: Department of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: John F
authors.initials: JF
authors.lastname: Eisses
authors.affiliation: Department of Surgery, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania.
authors.forename: Angela
authors.initials: A
authors.lastname: Criscimanna
authors.affiliation: Department of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Zachary R
authors.initials: ZR
authors.lastname: Dionise
authors.affiliation: Department of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Abrahim I
authors.initials: AI
authors.lastname: Orabi
authors.affiliation: Department of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Tanveer A
authors.initials: TA
authors.lastname: Javed
authors.affiliation: Department of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Sheharyar
authors.initials: S
authors.lastname: Sarwar
authors.affiliation: Department of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Shunqian
authors.initials: S
authors.lastname: Jin
authors.affiliation: Department of Pathology, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Pathology, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania.
authors.forename: Sucha
authors.initials: S
authors.lastname: Singh
authors.affiliation: Department of Pathology, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania.
authors.forename: Minakshi
authors.initials: M
authors.lastname: Poddar
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Amy W
authors.initials: AW
authors.lastname: Davis
authors.affiliation: Biomedical and Electrical and Computer Engineering, Center for Bioimage Informatics, Carnegie Mellon University, Pittsburgh, Pennsylvania.
authors.forename: Akif Burak
authors.initials: AB
authors.lastname: Tosun
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: John A
authors.initials: JA
authors.lastname: Ozolek
authors.affiliation: Department of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Lowe
authors.affiliation: Department of Pathology, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Satdarshan P
authors.initials: SP
authors.lastname: Monga
authors.affiliation: Biomedical and Electrical and Computer Engineering, Center for Bioimage Informatics, Carnegie Mellon University, Pittsburgh, Pennsylvania.
authors.forename: Gustavo K
authors.initials: GK
authors.lastname: Rohde
authors.affiliation: Department of Surgery, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania.
authors.forename: Farzad
authors.initials: F
authors.lastname: Esni
authors.affiliation: Department of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address: sohail.husain@chp.edu.
authors.forename: Sohail Z
authors.initials: SZ
authors.lastname: Husain
mesh_terms: D061354:Acinar Cells / Q000187:drug effects* / Q000473:pathology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000633:toxicity*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002108:Ceruletide; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000502:physiology*; D008297:Male; D051379:Mice; D010179:Pancreas / Q000502:physiology; D010195:Pancreatitis / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D012038:Regeneration / Q000187:drug effects; D015854:Up-Regulation; D014635:Valproic Acid / Q000494:pharmacology / Q000633:toxicity*
chemical_list: D000927:Anticonvulsants; D056572:Histone Deacetylase Inhibitors; D014635:Valproic Acid; D002108:Ceruletide; D006655:Histone Deacetylases