Synergies of heparin and second messengers pathways involved in tissue-specific gene expression in hepatocytes.

We have investigated the effect of soluble or extracellular-matrix (ECM) -bound heparin in conjunction with various second messenger pathways on cell proliferation and tissue-specific gene expression in primary cultures of hepatocytes. None of the combinations of heparin and second messenger stimulators or inhibitors had an effect on hepatocyte proliferation. Soluble heparin enhanced albumin expression in hepatocytes. Activation of protein kinase C, as well as an increase in intracellular cAMP, abolished this increase in albumin expression in the presence of heparin. When hepatocytes were plated on hepatocyte-derived ECM, containing highly sulfated heparan sulfate chains, activation of protein kinase C and an increase in intracellular cAMP strongly reduced albumin expression in hepatocytes. When heparan sulfate chains were removed from the ECM by heparinase treatment, activation of protein kinase C and increased cAMP were less inhibitory for albumin expression in hepatocytes. Inhibition of tyrosine kinases did not affect the induction of albumin mRNA by heparin. We conclude that heparin induces albumin expression in hepatocytes and activation of protein kinase C or increased intracellular cAMP antagonize this effect. ECM-bound heparan sulfates do not act in the same manner as soluble heparin.