Assessment of Response to Beta-Blockers by Expression of βArr2 and RhoA/ROCK2 in Antrum Mucosa in Cirrhotic Patients

J Hepatol. 2016 Jun;64(6):1265-73. doi: 10.1016/j.jhep.2016.01.022. Epub 2016 Jan 28.

Abstract

Background & aims: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Beta-blocker; Gastric mucosa; Portal hypertension; Vasoactive proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Antagonists / therapeutic use*
  • Adult
  • Aged
  • Female
  • Gastric Mucosa / metabolism*
  • Hemodynamics / drug effects
  • Humans
  • Liver Cirrhosis / drug therapy*
  • Liver Cirrhosis / physiopathology
  • Male
  • Middle Aged
  • Pyloric Antrum / metabolism*
  • RNA, Messenger / analysis
  • beta-Arrestin 2 / genetics*
  • rho-Associated Kinases / genetics*
  • rhoA GTP-Binding Protein / genetics*

Substances

  • Adrenergic beta-Antagonists
  • RNA, Messenger
  • beta-Arrestin 2
  • RHOA protein, human
  • ROCK2 protein, human
  • rho-Associated Kinases
  • rhoA GTP-Binding Protein