Alpha 2A adrenergic receptor antagonism reduces fibrosis, inflammation and portal hypertension in models of chronic liver disease.

BACKGROUND & AIMS: Sympathetic nervous system over-activity is associated with liver disease progression and development of portal hypertension, influencing systemic inflammation. This study examined the role of the sympathetic alpha-2A adrenergic receptor (ADRA2a) and its antagonism in hepatic stellate cell (HSC) activation, a key event in fibrosis progression, in experimental metabolic dysfunction-associated steatohepatitis (MASH) and in portal pressure elevation in a cirrhotic-rat model.

METHODS

An established bile duct ligation (BDL)-induced cirrhosis model (n = 14) was used to assess ADRA2a's role in portal hypertension through acute treatment with two ADRA2A antagonists (BRL44408 and yohimbine). Human (h)HSCs were incubated with either an ADRA2a agonist (guanfacine) or antagonist (BRL44408), to determine whether ADRA2a modulation altered HSC activation. We also investigated ADRA2a expression in patients with MASH fibrosis (n = 15) and conducted a longer-term yohimbine treatment study in a diet-induced MASH rodent model (n = 24).

RESULTS

BRL44408 reduced portal pressure in BDL rats (12 ± 3 vs. 18 ± 4 mmHg; p <0.0001) while preserving mean arterial pressure (102 ± 16 vs. 93 ± 13 mmHg, p = 0.13). This was associated with (i) restored eNOS phosphorylation towards control levels and reduced caveolin-1 expression (p <0.05), and (ii) reduced hepatic inflammation and Kuppfer cell activation (p <0.001). Moreover, guanfacine stimulation of hHSCs increased their contractility, which was attenuated by BRL44408 (p <0.001). ADRA2A mRNA expression was increased in both patients with MASH fibrosis, and MASH rats. In MASH rats, yohimbine treatment reduced fibrosis, as measured by collagen proportional area (p <0.01).

CONCLUSIONS

ADRA2A expression is increased in two experimental models of liver disease and in patients with MASH fibrosis, and it appears to contribute to the pathogenesis of portal hypertension and fibrogenesis. These findings suggest that ADRA2A antagonism may represent a potential therapeutic strategy for treating portal hypertension and fibrosis progression.

IMPACT AND IMPLICATIONS: Managing fibrosis progression and portal hypertension remains a major challenge in liver disease, with fewer than 60% of patients responding to current non-selective beta-blocker therapy, despite clear evidence of increased sympathetic activation as liver disease advances. We show that the alpha-2A adrenergic receptor (ADRA2A) may represent an important pathway in hepatic stellate cell activation and may also influence additional mechanisms that regulate elevated portal pressure. These findings provide an alternative approach to beta-blockade for portal hypertension, which is limited by reductions in cardiac output and liver blood flow that can be problematic in patients with advanced disease. Data from two different rodent models support consideration of a translational clinical study of ADRA2A antagonism in portal hypertension and further investigation into the mechanisms by which ADRA2A antagonism affects metabolic dysfunction-associated steatotic liver disease.