Heme oxygenase-1 gene expression in pericentral hepatocytes through beta1-adrenoceptor stimulation.

ABSTRACT

Induction of heme oxygenase (HO)-1 may confer hepatocellular protection, e.g., in reperfusion injury. Previous reports suggest that intracellular cAMP up-regulates HO-1. The aim of the present study was to assess the role of adrenoceptor agonists as a means to induce HO-1 and to assess molecular mechanisms of HO-1 gene expression by adrenoceptor agonists. Induction of HO-1 in primary cultures of hepatocytes and in rat liver in vivo was assessed by Northern blot, Western blot, and immunohistochemistry. The beta-receptor agonists (+/-)isoproterenol and (-)isoproterenol induced HO-1 in primary cultures of hepatocytes but not the inactive enantiomer (+)isoproterenol. No induction of HO-1 was observed after alpha1, alpha2, beta2, or beta 3 agonists. beta1-Receptor agonists dobutamine and xamoterol induced HO-1 dose dependently, whereas the beta1-receptor antagonist metoprolol attenuated HO-1 induction by beta1-receptor agonists. Furthermore, 8 Br-cAMP and forskolin induced HO-1. Inhibition of protein kinase A (PKA) abolished induction by dobutamine and 8 Br-cAMP. Parallel changes were observed for the transcription factor AP-1. In vivo infusion of dobutamine for 6 h induced HO-1 in rat livers. Immunohistochemical detection of HO-1 revealed a pericentral expression pattern of HO-1 in hepatocytes, i.e., the area at risk for ischemia/reperfusion injury. These results suggest induction of HO-1 by beta1-adrenoceptor agonists via the PKA pathway in hepatocytes, reflecting a potential means for "pharmacological preconditioning."