β 2 -Adrenergic receptor-selective agonist clenbuterol prevents Fas-induced liver apoptosis and death in mice

• Published in: American journal of physiology: Gastrointestinal and liver physiology 1999-03, Vol.276 (3), p.G647-G654
• Main Authors: André, Claudine, Couton, Dominique, Gaston, Jesintha, Erraji, Loubna, Renia, Laurent, Varlet, Paule, Briand, Pascale, Guillet, Jean-Gérard
• Format: Article
• Language: English
• ISSN: 0193-1857; 1522-1547
• DOI: 10.1152/ajpgi.1999.276.3.G647

Stimulation of the cAMP-signaling pathway modulates apoptosis in several cell types and inhibits Jo2-mediated apoptosis in cultured rat hepatocytes. No information is yet available as to whether the hepatic β -adrenergic receptor (AR) expression level, including β -AR-dependent adenylyl cyclase activation, modulates hepatocyte sensitivity to apoptosis in vivo or whether this sensitivity can be modified by β -AR ligands. We have examined this using C57BL/6 mice, in which hepatic β -AR densities are low, and transgenic F28 mice, which overexpress β -ARs and have elevated basal liver adenylyl cyclase activity. The F28 mice were resistant to Jo2-induced liver apoptosis and death. The β-AR antagonist propranolol sensitized the F28 livers to Jo2. In normal mice clenbuterol, a β -AR-specific agonist, considerably reduced Jo2-induced liver apoptosis and death; salbutamol, another β -AR-selective agonist, also reduced Jo2-induced apoptosis and retarded death but with less efficacy than clenbuterol; and propranolol blocked the protective effect of clenbuterol. This indicates that the expression level of functional β -ARs modulates Fas-regulated liver apoptosis and that this apoptosis can be inhibited in vivo by giving β -AR agonists. This may well form the basis for a new therapeutic approach to diseases involving abnormal apoptosis.