1999/03/01 by Claudine André, Dominique Couton, Jesintha Gaston +5
paper · 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 2 -adrenergic receptor (AR) expression level, including β 2 -AR-dependent adenylyl cyclase activation, modulates hepatocyte sensitivity to apoptosis in vivo or whether this sensitivity can be modified by β 2 -AR ligands. We have examined this using C57BL/6 mice, in which hepatic β 2 -AR densities are low, and transgenic F28 mice, which overexpress β 2 -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 2 -AR-specific agonist, considerably reduced Jo2-induced liver apoptosis and death; salbutamol, another β 2 -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 2 -ARs modulates Fas-regulated liver apoptosis and that this apoptosis can be inhibited in vivo by giving β 2 -AR agonists. This may well form the basis for a new therapeutic approach to diseases involving abnormal apoptosis.