EFFECT OF PRESSURE AND VOLUME OVERLOAD ON PROTOONCOGENE EXPRESSION IN THE ISOLATED WORKING RAT-HEART

Objective: The aim was to study the effect of pressure and volume overload on the expression of the proto-oncogenes, c-fos and c-myc, in isolated perfused working rat hearts and to compare these results with the known effects of noradrenaline. Methods: Working rat hearts were obtained by converting the Langendorff preparation into the working mode by perfusion through the left atrium. Using specific cDNA clones, the mRNAs of c-fos and c-myc were measured by northern blots and quantified with densitometry. Total RNA was isolated from hearts after stimulation with noradrenaline (3 x 10(-8) M), after increasing afterload from 80 to 100 cm H2O, and left atrial filling pressure (preload) from 8 to 16 cm H2O for 15, 30, 60, 90, and 120 min, respectively. Results: The mRNAs of c-fos and c-myc were not detectable in freshly excised rat hearts. When the hearts were perfused in the working mode for 15, 30, 60, 90, and 120 min, c-fos and c-myc mRNAs were measurable, and these mRNA levels served as control baseline values that were set at 100%. When noradrenaline was infused, c-fos mRNA was increased fivefold after 30, threefold after 60, and 3.8-fold after 90 min. The mRNA of c-myc was increased 1.8-fold after 60 min and 3.8-fold after 90 min. The increase in afterload induced a threefold increase of c-fos mRNA after 30 min and a threefold increase of c-myc mRNA after 90 min. When preload was increased, c-fos mRNA rose 1.8-fold after 30 min, and c-myc mRNA twofold after 60 min and 2.8-fold after 90 min compared to the controls. Conclusions: Pressure and volume overload have effects on the expression of c-fos and c-myc mRNA that are similar to those obtained with noradrenaline stimulation which induced the most pronounced signals. Our time course studies showed that c-fos mRNA always rose before c-myc mRNA. This common sequential induction pattern may have important signal function in the processes that trigger the development of cardiac hypertrophy.