Abstract
Introduction: Recent animal studies have shown that the alternate renin-angiotensin system (RAS) consisting of angiotensin-converting enzyme 2 (ACE2), angiotensin-(1–7) (Ang-(1–7)) and the Mas receptor is upregulated in cirrhosis and contributes to splanchnic vasodilatation and portal hypertension. To determine the potential relevance of these findings to human liver disease, we evaluated its expression and relationship to the patients’ clinical status in subjects with cirrhosis. Methods: Blood sampling from peripheral and central vascular beds was performed intra-operatively for cirrhotic patients at the time of liver transplantation (LT) or trans-jugular intra-hepatic portosystemic shunt (TIPS) procedures to measure angiotensin II (Ang II) and Ang-(1–7) peptide levels and ACE and ACE2 enzyme activity. Relevant clinical and hemodynamic data were recorded pre-operatively for all subjects and peripheral blood sampling was repeated 3 months or later post-operatively. Results: Ang-(1–-7) and ACE2 activity were up-regulated more than twofold in cirrhotic subjects both at the time of LT and TIPS and levels returned to comparable levels as control subjects post-transplantation. Ang-(1–7) levels correlated positively with the degree of liver disease severity, as measured by the model for an end-stage liver disease (MELD) and also with clinical parameters of pathological vasodilatation including cardiac output (CO). There were strong correlations found between the ACE2:ACE and the Ang-(1–7):Ang II ratio highlighting the inter-dependence of the alternate and classical arms of the RAS and thus their potential impact on vascular tone. Conclusions: In human cirrhosis, the alternate RAS is markedly upregulated and the activation of this system is associated strongly with features of the hyperdynamic circulation in advanced human cirrhosis.
Highlights
Recent animal studies have shown that the alternate renin-angiotensin system (RAS) consisting of angiotensin-converting enzyme 2 (ACE2), angiotensin-(1–7) (Ang-(1–7)) and the Mas receptor is upregulated in cirrhosis and contributes to splanchnic vasodilatation and portal hypertension
These findings suggest that activation of the alternate arm of the RAS may play an important role in mediating vasodilatation in cirrhosis
In order to further explore the concept of alternate RAS activation and its potential impact upon vascular pathophysiology in human cirrhosis, we measured the circulatory components of the contemporary RAS and important clinical parameters in a large cohort of cirrhotic patients who were undergoing either liver transplantation or a trans-jugular intra-hepatic portosystemic shunt (TIPs) procedure
Summary
Vasodilatation of the splanchnic circulation plays a pivotal role in the development of portal hypertension and the hyperdynamic circulatory state in human cirrhosis [1]. Our understanding of the RAS has evolved in recent times following the discovery of an ‘alternate’ counter-regulatory arm of the RAS Within this alternate arm, the angiotensin-converting enzyme 2 (ACE2), a homolog of ACE expressed by the vascular endothelium and liver parenchymal cells, [12,13,14] degrades Ang II generating the Ang-(1–7) peptide [13,14,15]. Our group has most recently shown that in experimental cirrhosis and portal hypertension upregulated ACE2 in the cirrhotic mesenteric vascular bed increased the production of the vasodilator Ang-(1–7) from Ang II breakdown and Ang-(1–7), in turn, markedly reduced vascular tone in the mesenteric bed of cirrhotic animals [15] These findings suggest that activation of the alternate arm of the RAS may play an important role in mediating vasodilatation in cirrhosis. In order to further explore the concept of alternate RAS activation and its potential impact upon vascular pathophysiology in human cirrhosis, we measured the circulatory components of the contemporary RAS and important clinical parameters in a large cohort of cirrhotic patients who were undergoing either liver transplantation or a trans-jugular intra-hepatic portosystemic shunt (TIPs) procedure
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
