TGF-BETA-1 UP-REGULATES THE MESSENGER-RNA FOR THE NA+ CA2+ EXCHANGER IN NEONATAL RAT CARDIAC MYOCYTES/

Northern analyses of neonatal cardiac myocytes demonstrated that TGF-b eta 1 (5 ng/ml) stimulates and IL-1 beta (5 ng/ml) decreases the stead y-state levels of the mRNA coding for the Na+/Ca2+ exchanger. This is in agreement with the effects of TGF-beta 1 and IL-1 beta on beating r ate and calcium uptake, suggesting that such effects might be mediated , at least partially, through up-regulation of the Na+/Ca2+ exchanger. Basal and TGF-beta 1 stimulated mRNA levels were inhibited by the PKC inhibitors H7 (10 mu M) and GF109203X (250 nhl). In addition, apigeni n (12.5 mu M), a MAP kinase inhibitor, was able to inhibit basal mRNA levels for the exchanger. Cycloheximide (35.5 mu M) had no effect on b asal mRNA levels for the exchanger but steady-state levels were dimini shed in cells treated with TGF-beta 1. Finally, actinomycin D (10 mu M ) inhibited both basal and TGF-beta 1 stimulated mRNA levels, though w ith a more pronounced effect in the presence of TGF-beta 1. These resu lts suggest that a complex mechanism of regulation exists for the exch anger and that PKC and possibly MAP kinases might be involved. The up- regulation of this important protein for calcium extrusion, induced by TGF-beta 1, might prepare cells to better overcome the calcium overlo ad which occurrs under cellular stress and might explain some of the c ytoprotective effects of TGF-beta 1.