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

Abstract

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-signalling alpha 2a adrenergic receptor (ADRA2a) and its antagonism on hepatic stellate cell (HSC) activation, as a key event in fibrosis progression in experimental metabolic dysfunction-associated steatohepatitis (MASH) and portal pressure elevation in a cirrhotic-rat model. An established bile duct ligation (BDL)-induced cirrhosis model (n=14) assessed ADRA2a's influence on portal hypertension by acute treatment with two different 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). BRL44408 reduced portal pressure in BDL rats (12&#xb1;3 vs. 18 &#xb1; 4 mmHg; p<0.0001) whilst preserving mean arterial pressure (102&#xb1;16 vs. 93&#xb1;13mmHg, p=0.13), associated with (i) restored eNOS phosphorylation towards control levels and reduced Caveolin-1 (p<0.05); (ii) reduced hepatic inflammation, and Kuppfer cell activation (p<0.001). Moreover, Guanfacine stimulation of hHSC increased their contractility, which was attenuated by BRL44408 (p<0.001). In MASH patients with fibrosis and in MASH rats, hepatic ADRA2a mRNA expression was increased. In MASH rats, Yohimbine treatment reduced fibrosis (collagen-proportionate-area); p < 0.01. Our study shows that ADRA2a expression is increased in two experimental models of liver disease and in patients with MASH fibrosis and is implicated in the pathogenesis of portal hypertension and fibrogenesis. These data suggest that ADRA2a antagonism could be a potential target for treating portal hypertension and fibrosis progression. Managing fibrosis progression and portal hypertension remain challenges in liver disease, with for example less than 60% responding to current beta blocker therapy despite clear evidence for increased sympathetic activation as liver disease advances. We show that ADRA2a receptors may represent an important pathway for stellate cell activation and also influence other mechanisms that regulate rise in portal pressure. The results provide an alternative approach to beta blockade therapy for portal hypertension with their implicit drop in cardiac output and liver blood flow, which provide challenges in patients with advanced disease. The data from this study in two different rodent models supports considerations for a clinical translational study of ADRAa antagonism in portal hypertension, and for further mechanisms to be elaborated on the effects of ADRA2a antagonism in MASLD.