Assessment of response to beta-blockers by expression of βArr2 and RhoA/ROCK2 in antrum mucosa in cirrhotic patients

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• 作者：Jonel Trebicka¹ ; ² ; ⁷ ; ^&dagger ; ; ^{jonel.trebicka@ukb.uni-bonn.de" class="auth_mail" title="E-mail the corresponding author} ; Matthias von Heydebrand¹ ; ^&dagger ; ; Jennifer Lehmann¹ ; Flemming Tofteng² ; Troels Busk³ ; Helle Lone Jensen⁴ ; Johan Rohde⁵ ; Thomas Reiberger⁶ ; Christian Mortensen² ; ³ ; Robert Schierwagen¹ ; Sabine Klein¹ ; Sø ; ren Mø ; ller³ ; ^&Dagger ; ; Flemming Bendtsen² ; ^&Dagger ; ; Aleksander Krag⁷ ; ^&Dagger ;
• 关键词：ALT ; alanine aminotransferase ; βArr2 ; beta-arrestin2 ; CCT ; central circulation time ; CO ; cardiac output ; CSPH ; clinical significant portal hypertension ; eNOS ; endothelial nitric oxide synthase ; FHVP ; free hepatic venous pressure ; HVPG ; hepatic vein pressure gradient ; INR ; international normalized ratio ; MAP ; mean arterial pressure ; MELD ; model for end-stage liver disease ; NO ; nitric oxide ; NSBB ; non-selective beta-blockers ; PHG ; portal hypertensive gastropathy ; PV ; plasma volume ; ROCK ; Rho-kinas
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：June 2016
• 年：2016
• 卷：64
• 期：6
• 页码：1265-1273
• 全文大小：1250 K

文摘

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 <10 mmHg, 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 >10 mmHg and HVPG >16 mmHg. 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.