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Am J Physiol Gastrointest Liver Physiol 276: G647-G654, 1999;
0193-1857/99 $5.00
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Vol. 276, Issue 3, G647-G654, March 1999

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

Claudine André1, Dominique Couton1, Jesintha Gaston2, Loubna Erraji1, Laurent Renia2, Paule Varlet3, Pascale Briand1, and Jean-Gérard Guillet2

1 Institut National de la Santé et de la Recherche Médicale (INSERM) U380, 2 INSERM U445, and 3 INSERM U363, Institut Cochin de Génétique Moléculaire, Université René Descartes, 75014 Paris, France

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

beta -adrenoceptor antagonist; C57BL/6 mouse; transgenic F28 mouse; anti-Fas monoclonal antibody


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