Limits...
Hemodynamic Effects of the Non-Peptidic Angiotensin-(1-7) Agonist AVE0991 in Liver Cirrhosis.

Klein S, Herath CB, Schierwagen R, Grace J, Haltenhof T, Uschner FE, Strassburg CP, Sauerbruch T, Walther T, Angus PW, Trebicka J - PLoS ONE (2015)

Bottom Line: Importantly, systemic effects were not observed.The non-peptidic agonist of Ang-(1-7), AVE0991, decreases portal pressure without influencing systemic pressure.Thus, although it does not inhibit fibrosis, AVE0991 may represent a promising new therapeutic strategy for lowering portal pressure.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.

ABSTRACT

Background & aims: Although in cirrhosis with portal hypertension levels of the vasoconstrictor angiotensin II are increased, this is accompanied by increased production of angiotensin (Ang)-(1-7), the endogenous ligand of the Mas receptor (MasR), which blunts hepatic fibrosis and decreases hepatic vascular resistance. Therefore, we investigated the effects of the non-peptidic Ang-(1-7) agonist, AVE0991, in experimental cirrhosis.

Methods: Cirrhosis was induced by bile duct ligation (BDL) or carbon tetrachloride (CCl4) intoxication. The coloured microsphere technique assessed portal and systemic hemodynamic effects of AVE0991 in vivo. Hepatic expression of eNOS, p-eNOS, iNOS, JAK2, ROCK and p-Moesin were analyzed by western blots. Activities of ACE and ACE2 were investigated fluorometrically. Moreover, fibrosis was assessed in BDL rats receiving AVE0991.

Results: In vivo, AVE0991 decreased portal pressure (PP) in both rat models of cirrhosis. Importantly, systemic effects were not observed. The hepatic effects of AVE0991 were based on upregulation of vasodilating pathways involving p-eNOS and iNOS, as well as by downregulation of the vasoconstrictive pathways (ROCK, p-Moesin). Short-term treatment with AVE0991 decreased the activity of ACE2, long-term treatment did not affect hepatic fibrosis in BDL rats.

Conclusions: The non-peptidic agonist of Ang-(1-7), AVE0991, decreases portal pressure without influencing systemic pressure. Thus, although it does not inhibit fibrosis, AVE0991 may represent a promising new therapeutic strategy for lowering portal pressure.

No MeSH data available.


Related in: MedlinePlus

Hepatic expression of vasodilatatory and vasoconstrictory proteins, gene expression levels of the MasR and ACE2 and the hepatic ACE2 activity in cirrhosis with and without acute AVE0991 treatment.(A) Hepatic protein expression of the endothelial NO synthase (eNOS) was not influenced by AVE0991 injection in BDL rats. Its active form p-eNOS was significantly increased in BDL and CCl4 intoxicated rats after AVE0991 injection. The hepatic inducible NOS (iNOS) was not changed significantly by AVE0991 injection in cirrhotic rats. The vasoconstrictory Rho-kinase (ROCK) protein and its activity, measured by the phosphorylation of its substrate Moesin (pMoesin), were decreased significantly after AVE0991 injection in BDL and CCl4 intoxicated rats. (B, C) Representive blots of protein expression levels (eNOS, p-eNOS, iNOS, ROCK, p-Moesin, GAPDH) in cirrhotic BDL and CCl4 intoxicated rats with and without AVE0991 injection. (D) The hepatic mRNA expression of the Mas receptor was slightly decreased in BDL and CCl4 intoxicated rats after AVE0991 injection but not significantly. (E) The mRNA expression of ACE2 was significantly decreased in livers of BDL and CCl4 intoxicated rats after AVE0991 injection. (F) The injection of AVE0991 induced a significant reduction of the hepatic ACE2 activity in all cirrhotic rats. All results of mRNA expression levels are shown as the quantification of qRT-PCR results, normalized to sham without AVE0991.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4583473&req=5

pone.0138732.g003: Hepatic expression of vasodilatatory and vasoconstrictory proteins, gene expression levels of the MasR and ACE2 and the hepatic ACE2 activity in cirrhosis with and without acute AVE0991 treatment.(A) Hepatic protein expression of the endothelial NO synthase (eNOS) was not influenced by AVE0991 injection in BDL rats. Its active form p-eNOS was significantly increased in BDL and CCl4 intoxicated rats after AVE0991 injection. The hepatic inducible NOS (iNOS) was not changed significantly by AVE0991 injection in cirrhotic rats. The vasoconstrictory Rho-kinase (ROCK) protein and its activity, measured by the phosphorylation of its substrate Moesin (pMoesin), were decreased significantly after AVE0991 injection in BDL and CCl4 intoxicated rats. (B, C) Representive blots of protein expression levels (eNOS, p-eNOS, iNOS, ROCK, p-Moesin, GAPDH) in cirrhotic BDL and CCl4 intoxicated rats with and without AVE0991 injection. (D) The hepatic mRNA expression of the Mas receptor was slightly decreased in BDL and CCl4 intoxicated rats after AVE0991 injection but not significantly. (E) The mRNA expression of ACE2 was significantly decreased in livers of BDL and CCl4 intoxicated rats after AVE0991 injection. (F) The injection of AVE0991 induced a significant reduction of the hepatic ACE2 activity in all cirrhotic rats. All results of mRNA expression levels are shown as the quantification of qRT-PCR results, normalized to sham without AVE0991.

Mentions: Following AVE0991 injection, cirrhotic BDL and CCl4 intoxicated rats with portal hypertension, showed no significant change in protein expression levels of hepatic eNOS, but increased hepatic protein levels of phosphorylated eNOS (p-eNOS) underlining the mechanism for the hepatic vasodilation in cirrhosis (Fig 3A–3C). By contrast, hepatic iNOS expression levels were not significantly influenced one hour after acute AVE0991 injection in cirrhotic rats. Sham-operated rats showed also no change in hepatic eNOS expression level of after AVE0991 injection, but hepatic iNOS expression levels were significantly decreased in sham-operated rats after AVE0991 injection (Fig A in S1 Figs).


Hemodynamic Effects of the Non-Peptidic Angiotensin-(1-7) Agonist AVE0991 in Liver Cirrhosis.

Klein S, Herath CB, Schierwagen R, Grace J, Haltenhof T, Uschner FE, Strassburg CP, Sauerbruch T, Walther T, Angus PW, Trebicka J - PLoS ONE (2015)

Hepatic expression of vasodilatatory and vasoconstrictory proteins, gene expression levels of the MasR and ACE2 and the hepatic ACE2 activity in cirrhosis with and without acute AVE0991 treatment.(A) Hepatic protein expression of the endothelial NO synthase (eNOS) was not influenced by AVE0991 injection in BDL rats. Its active form p-eNOS was significantly increased in BDL and CCl4 intoxicated rats after AVE0991 injection. The hepatic inducible NOS (iNOS) was not changed significantly by AVE0991 injection in cirrhotic rats. The vasoconstrictory Rho-kinase (ROCK) protein and its activity, measured by the phosphorylation of its substrate Moesin (pMoesin), were decreased significantly after AVE0991 injection in BDL and CCl4 intoxicated rats. (B, C) Representive blots of protein expression levels (eNOS, p-eNOS, iNOS, ROCK, p-Moesin, GAPDH) in cirrhotic BDL and CCl4 intoxicated rats with and without AVE0991 injection. (D) The hepatic mRNA expression of the Mas receptor was slightly decreased in BDL and CCl4 intoxicated rats after AVE0991 injection but not significantly. (E) The mRNA expression of ACE2 was significantly decreased in livers of BDL and CCl4 intoxicated rats after AVE0991 injection. (F) The injection of AVE0991 induced a significant reduction of the hepatic ACE2 activity in all cirrhotic rats. All results of mRNA expression levels are shown as the quantification of qRT-PCR results, normalized to sham without AVE0991.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4583473&req=5

pone.0138732.g003: Hepatic expression of vasodilatatory and vasoconstrictory proteins, gene expression levels of the MasR and ACE2 and the hepatic ACE2 activity in cirrhosis with and without acute AVE0991 treatment.(A) Hepatic protein expression of the endothelial NO synthase (eNOS) was not influenced by AVE0991 injection in BDL rats. Its active form p-eNOS was significantly increased in BDL and CCl4 intoxicated rats after AVE0991 injection. The hepatic inducible NOS (iNOS) was not changed significantly by AVE0991 injection in cirrhotic rats. The vasoconstrictory Rho-kinase (ROCK) protein and its activity, measured by the phosphorylation of its substrate Moesin (pMoesin), were decreased significantly after AVE0991 injection in BDL and CCl4 intoxicated rats. (B, C) Representive blots of protein expression levels (eNOS, p-eNOS, iNOS, ROCK, p-Moesin, GAPDH) in cirrhotic BDL and CCl4 intoxicated rats with and without AVE0991 injection. (D) The hepatic mRNA expression of the Mas receptor was slightly decreased in BDL and CCl4 intoxicated rats after AVE0991 injection but not significantly. (E) The mRNA expression of ACE2 was significantly decreased in livers of BDL and CCl4 intoxicated rats after AVE0991 injection. (F) The injection of AVE0991 induced a significant reduction of the hepatic ACE2 activity in all cirrhotic rats. All results of mRNA expression levels are shown as the quantification of qRT-PCR results, normalized to sham without AVE0991.
Mentions: Following AVE0991 injection, cirrhotic BDL and CCl4 intoxicated rats with portal hypertension, showed no significant change in protein expression levels of hepatic eNOS, but increased hepatic protein levels of phosphorylated eNOS (p-eNOS) underlining the mechanism for the hepatic vasodilation in cirrhosis (Fig 3A–3C). By contrast, hepatic iNOS expression levels were not significantly influenced one hour after acute AVE0991 injection in cirrhotic rats. Sham-operated rats showed also no change in hepatic eNOS expression level of after AVE0991 injection, but hepatic iNOS expression levels were significantly decreased in sham-operated rats after AVE0991 injection (Fig A in S1 Figs).

Bottom Line: Importantly, systemic effects were not observed.The non-peptidic agonist of Ang-(1-7), AVE0991, decreases portal pressure without influencing systemic pressure.Thus, although it does not inhibit fibrosis, AVE0991 may represent a promising new therapeutic strategy for lowering portal pressure.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.

ABSTRACT

Background & aims: Although in cirrhosis with portal hypertension levels of the vasoconstrictor angiotensin II are increased, this is accompanied by increased production of angiotensin (Ang)-(1-7), the endogenous ligand of the Mas receptor (MasR), which blunts hepatic fibrosis and decreases hepatic vascular resistance. Therefore, we investigated the effects of the non-peptidic Ang-(1-7) agonist, AVE0991, in experimental cirrhosis.

Methods: Cirrhosis was induced by bile duct ligation (BDL) or carbon tetrachloride (CCl4) intoxication. The coloured microsphere technique assessed portal and systemic hemodynamic effects of AVE0991 in vivo. Hepatic expression of eNOS, p-eNOS, iNOS, JAK2, ROCK and p-Moesin were analyzed by western blots. Activities of ACE and ACE2 were investigated fluorometrically. Moreover, fibrosis was assessed in BDL rats receiving AVE0991.

Results: In vivo, AVE0991 decreased portal pressure (PP) in both rat models of cirrhosis. Importantly, systemic effects were not observed. The hepatic effects of AVE0991 were based on upregulation of vasodilating pathways involving p-eNOS and iNOS, as well as by downregulation of the vasoconstrictive pathways (ROCK, p-Moesin). Short-term treatment with AVE0991 decreased the activity of ACE2, long-term treatment did not affect hepatic fibrosis in BDL rats.

Conclusions: The non-peptidic agonist of Ang-(1-7), AVE0991, decreases portal pressure without influencing systemic pressure. Thus, although it does not inhibit fibrosis, AVE0991 may represent a promising new therapeutic strategy for lowering portal pressure.

No MeSH data available.


Related in: MedlinePlus