Original ResearchFull Report: Basic and Translational—LiverActivation of the Mas Receptor by Angiotensin-(1–7) in the Renin–Angiotensin System Mediates Mesenteric Vasodilatation in Cirrhosis
Section snippets
Human Samples
Experimental procedures to obtain human vessels were approved by the Human Ethics Committee of the University of Bonn 2002/01. During liver transplantation, samples of hepatic arteries from patients with alcohol-induced cirrhosis were obtained (n = 7) and compared with hepatic artery samples from noncirrhotic organ donors, which served as controls (n = 7). Liver samples were obtained from cirrhotic liver explants (n = 8) and compared with healthy liver samples from patients undergoing other
Expression of MasR and ACE2 Is Increased in Splanchnic Vascular Wall in Cirrhotic Rats and Humans
The Ang-(1−7) receptor, MasR, protein was significantly increased in mesenteric arterial vessels from cirrhotic BDL rats (Figure 1A). The findings were similar in human hepatic arteries, where transplant recipient vessels (cirrhotic vessels) contained more MasR protein compared with noncirrhotic donor vessels (control vessels) (Figure 1A).
In contrast, expression of AT1R in splanchnic vessels from cirrhotic animals and cirrhotic patients was not significantly different from control (P = .48 and P
Discussion
This study uncovers a new pathophysiological mechanism of splanchnic vasodilatation, which contributes to portal hypertension in cirrhosis (Figure 7). Our results demonstrate that, in experimental and human cirrhosis, the expression and activity of splanchnic vascular ACE2 are increased. Consequently, local production of the vasodilator and MasR-agonist, Ang-(1−7), is elevated. In addition, locally increased production of Ang-(1−7), together with augmented splanchnic vascular expression of
Acknowledgments
The authors gratefully acknowledge Zhijuan Jia, Gudrun Hack, Silke Bellinghausen, and Stephanie Müller for excellent technical assistance.
References (38)
- et al.
Angiotensin II induces contraction and proliferation of human hepatic stellate cells
Gastroenterology
(2000) - et al.
A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase
J Biol Chem
(2000) - et al.
Upregulation of hepatic angiotensin-converting enzyme 2 (ACE2) and angiotensin-(1−7) levels in experimental biliary fibrosis
J Hepatol
(2007) - et al.
Nitric oxide mediates hyporeactivity to vasopressors in mesenteric vessels of portal hypertensive rats
Gastroenterology
(1992) - et al.
Contractile hyporesponsiveness of hepatic arteries in humans with cirrhosis: evidence for a receptor-specific mechanism
Hepatology
(2001) - et al.
Expression of the mouse and rat mas proto-oncogene in the brain and peripheral tissues
FEBS Lett
(1995) - et al.
PKA-mediated effect of MAS receptor in counteracting angiotensin II-stimulated renal Na+-ATPase
Arch Biochem Biophys
(2010) - et al.
Regulation of endothelial and myocardial NO synthesis by multi-site eNOS phosphorylation
J Mol Cell Cardiol
(2007) - et al.
Angiotensin receptors: form and function and distribution
Int J Biochem Cell Biol
(2003) - et al.
Renin-angiotensin-aldosterone inhibitors in the reduction of portal pressure: a systematic review and meta-analysis
J Hepatol
(2010)
Hemodynamic effects of the angiotensin II receptor antagonist irbesartan in patients with cirrhosis and portal hypertension
Gastroenterology
Plasma noradrenaline in cirrhosis: a study of kinetics and temporal relationship to ascites formation
Eur J Clin Invest
Systemic infusion of angiotensin II exacerbates liver fibrosis in bile duct-ligated rats
Hepatology
A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9
Circ Res
Synergistic effect of angiotensin-(1−7) on bradykinin arteriolar dilation in vivo
Peptides
Angiotensin-(1−7), an alternative metabolite of the renin-angiotensin system, is up-regulated in human liver disease and has antifibrotic activity in the bile-duct-ligated rat
Clin Sci
Relationship between angiotensin-(1−7) and angiotensin II correlates with hemodynamic changes in human liver cirrhosis
World J Gastroenterol
Chronic liver injury in rats and humans upregulates the novel enzyme angiotensin converting enzyme 2
Gut
The effect of sympathetic nerve stimulation of vasoconstrictor responses in perfused mesenteric blood vessels of the rat
J Physiol
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Author names in bold designate shared co-first authorship.
Conflicts of interest The authors disclose no conflicts.
Funding This work was funded in part by a National Health and Medical Research Council of Australia Project Grant and by Deutsche Forschungsgemeinschaft (SFB TRR 57, P18).
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Authors share co-first authorship
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Authors share co-senior authorship.