beta2-adrenergic receptor-selective agonist clenbuterol prevents Fas-induced liver apoptosis and death in mice.

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 beta2-adrenergic receptor (AR) expression level, including beta2-AR-dependent adenylyl cyclase activation, modulates hepatocyte sensitivity to apoptosis in vivo or whether this sensitivity can be modified by beta2-AR ligands. We have examined this using C57BL/6 mice, in which hepatic beta2-AR densities are low, and transgenic F28 mice, which overexpress beta2-ARs and have elevated basal liver adenylyl cyclase activity. The F28 mice were resistant to Jo2-induced liver apoptosis and death. The beta-AR antagonist propranolol sensitized the F28 livers to Jo2. In normal mice clenbuterol, a beta2-AR-specific agonist, considerably reduced Jo2-induced liver apoptosis and death; salbutamol, another beta2-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 beta2-ARs modulates Fas-regulated liver apoptosis and that this apoptosis can be inhibited in vivo by giving beta2-AR agonists. This may well form the basis for a new therapeutic approach to diseases involving abnormal apoptosis.