title: Assessment of response to beta-blockers by expression of βArr2 and RhoA/ROCK2 in antrum mucosa in cirrhotic patients.
abstract: Non-selective beta-blockers (NSBB) are first choice for prevention of variceal bleeding. But possible deleterious effects in refractory ascites and frequent non-response are clinical drawbacks. Since levels of vasoactive proteins in antrum mucosa reflect vascular dysfunction in cirrhosis, these expression levels might also reflect hemodynamic response to NSBB.
  
  
  
  Biopsies from the gastric and duodenal mucosa of 25 patients with cirrhosis were collected and the hepatic venous pressure gradient (HVPG) was measured before and after an acute propranolol challenge. Transcription and protein expression of Ras homolog family member A (RhoA), Rho-kinase (ROCK)2, beta-arrestin2 (βArr2), endothelial nitric oxide synthase (eNOS) and the phosphorylation of downstream effectors VASP and moesin were analyzed using PCR and Western blot. Further 21 patients on NSBB were evaluated on their follow up for events of variceal bleeding defined as non-response.
  
  
  
  Ten patients showed HVPG <10mmHg, further seven patients showed significant hemodynamic response to NSBB, whereas eight patients were non-responders. The mucosal transcription of vasoactive proteins was higher in antrum mucosa compared to corpus and duodenum. The transcriptional levels of vasoactive proteins were higher in patients with HVPG >10mmHg and HVPG >16mmHg. Interestingly, mRNA levels of RhoA and ROCK2 were lower in patients with large varices at endoscopy. Moreover, RhoA and ROCK2 transcription correlated with the decrease of HVPG after acute NSBB challenge. Finally, acute and long-term non-responders showed lower expression of βArr2 in antrum mucosa.
  
  
  
  This study shows for the first time that the expression of βArr2 in antrum mucosa biopsies might reflect the hemodynamic response to NSBB and their long-term protective effect. This finding might offer an easy approach at upper endoscopy to facilitate the decision to treat with NSBB if varices are present.
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany; Gastrounit, Medical Division, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Gastroenterology, Odense University Hospital, University of Southern Denmark, Odense, Denmark. Electronic address: jonel.trebicka@ukb.uni-bonn.de.
authors.forename: Jonel
authors.initials: J
authors.lastname: Trebicka
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: von Heydebrand
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lehmann
authors.affiliation: Gastrounit, Medical Division, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Flemming
authors.initials: F
authors.lastname: Tofteng
authors.affiliation: Centre of Functional Imaging and Research, Department of Clinical Physiology and Nuclear Medicine, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Troels
authors.initials: T
authors.lastname: Busk
authors.affiliation: Department of Pathology, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Helle Lone
authors.initials: HL
authors.lastname: Jensen
authors.affiliation: Department of Hepatology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Johan
authors.initials: J
authors.lastname: Rohde
authors.affiliation: Department of Internal Medicine III, Division of Gastroenterology & Hepatology, Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Reiberger
authors.affiliation: Gastrounit, Medical Division, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark; Centre of Functional Imaging and Research, Department of Clinical Physiology and Nuclear Medicine, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Mortensen
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Schierwagen
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Klein
authors.affiliation: Centre of Functional Imaging and Research, Department of Clinical Physiology and Nuclear Medicine, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Møller
authors.affiliation: Gastrounit, Medical Division, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Flemming
authors.initials: F
authors.lastname: Bendtsen
authors.affiliation: Department of Gastroenterology, Odense University Hospital, University of Southern Denmark, Odense, Denmark.
authors.forename: Aleksander
authors.initials: A
authors.lastname: Krag
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism*; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011706:Pyloric Antrum / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D000071560:beta-Arrestin 2 / Q000235:genetics*; D054460:rho-Associated Kinases / Q000235:genetics*; D020742:rhoA GTP-Binding Protein / Q000235:genetics*
chemical_list: D000319:Adrenergic beta-Antagonists; D012333:RNA, Messenger; D000071560:beta-Arrestin 2; C066737:RHOA protein, human; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein
keywords: Beta-blocker; Gastric mucosa; Portal hypertension; Vasoactive proteins