A farnesyltransferase inhibitor attenuates cardiac myocyte hypertrophy andgene expression

The overexpression of either oncogenic ras or calmodulin in cardiac myocyte s can elicit a hypertrophic response, albeit their recruitment by physiolog ically relevant stimuli remains unresolved. The present study utilized a ph armacological approach to examine the role of ras and calmodulin in norepin ephrine- and endothelin-1-stimulated hypertrophy of neonatal rat cardiac my ocytes. The pretreatment of cardiac myocytes with the farnesyltransferase i nhibitor BMS-191563 (25 mu M) increased the level of unfarnesylated ras in the cytosolic fraction, and caused a concomitant 42+/-2% decrease in immuno detectable farnesylated ras in the particulate fraction. In parallel, BMS-1 91563 pretreatment inhibited norepinephrine-medialed H-3-leucine uptake (80 +/-10% decrease: n=6; P<0.01). whereas a significant but less pronounced ef fect on the endothelin-1 response (46+/-6% decrease: n=6: P<0.05) was obser ved. The calmodulin inhibitor W7 caused a 50+/-10% decrease (n=8; P<0.05) o f norepinephrine stimulated protein synthesis, whereas the endothelin-l res ponse was unaffected. Consistent with the recruitment of ras, BMS-191563 pr etreatment attenuated norepinephrine and endothelin-1-stimulated extracellu lar signal-regulated kinase (ERK) activity. However, PD098059-mediated inhi bition of MEK-dependent stimulation of ERK did not: alter the hypertrophic response of either agonist, At the molecular level, the pretreatment with t ither BMS-191563 or W7 attenuated the norepinephrine-mediated increase of p repro-ANP and -BNP mRNA, Likewise, BMS-191563 caused a significant decrease of endothelin-1-mediated expression of the natriuretic peptide mRNAs, but to a lesser extent, as compared to norepinephrine. Thus, the present study has shown the treatment of neonatal rat cardiac myocytes with a farnesyltra nsferase inhibitor can attenuate the hypertrophic phenotype in response to physiologically relevant stimuli, thereby supporting role of the small GTP- binding protein ras. Moreover, these data further suggest alternative ras-i ndependent signaling pathways are also implicated in the hypertrophic respo nse, albeit, there appears to exist a stimulus-specific heterogeneity in th eir recruitment. (C) 2000 Academic Press.