title: A farnesyltransferase inhibitor attenuates cardiac myocyte hypertrophy and gene expression.
abstract: The overexpression of either oncogenic ras or calmodulin in cardiac myocytes can elicit a hypertrophic response, albeit their recruitment by physiologically relevant stimuli remains unresolved. The present study utilized a pharmacological approach to examine the role of ras and calmodulin in norepinephrine- and endothelin-1-stimulated hypertrophy of neonatal rat cardiac myocytes. The pretreatment of cardiac myocytes with the farnesyltransferase inhibitor BMS-191563 (25 microM) increased the level of unfarnesylated ras in the cytosolic fraction, and caused a concomitant 42 +/- 2% decrease in immunodetectable farnesylated ras in the particulate fraction. In parallel, BMS-191563 pretreatment inhibited norepinephrine-mediated 3H-leucine uptake (80 +/- 10% decrease: n = 6; P<0.01), whereas a significant but less pronounced effect on the endothelin-1 response (46 +/- 6% decrease: n = 6; P<0.05) was observed. The calmodulin inhibitor W7 caused a 50 +/- 10% decrease (n = 8; P<0.05) of norepinephrine stimulated protein synthesis, whereas the endothelin-1 response was unaffected. Consistent with the recruitment of ras, BMS-191563 pretreatment attenuated norepinephrine and endothelin-1-stimulated extracellular signal-regulated kinase (ERK) activity. However, PD098059-mediated inhibition of MEK-dependent stimulation of ERK did not alter the hypertrophic response of either agonist. At the molecular level, the pretreatment with either BMS-191563 or W7 attenuated the norepinephrine-mediated increase of prepro-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 farnesyltransferase inhibitor can attenuate the hypertrophic phenotype in response to physiologically relevant stimuli, thereby supporting a role of the small GTP-binding protein ras. Moreover, these data further suggest alternative ras-independent signaling pathways are also implicated in the hypertrophic response, albeit, there appears to exist a stimulus-specific heterogeneity in their recruitment.
authors.affiliation: Université de Montréal, Departément de Physiologie et Biochimie, et l'Institut de Cardiologie de Montréal, Québec, Canada. calderon@icm.umontreal.ca
authors.forename: A
authors.initials: A
authors.lastname: Calderone
authors.forename: N
authors.initials: N
authors.lastname: Abdelaziz
authors.forename: F
authors.initials: F
authors.lastname: Colombo
authors.forename: K L
authors.initials: KL
authors.lastname: Schreiber
authors.forename: H
authors.initials: H
authors.lastname: Rindt
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics*; D002147:Calmodulin / Q000494:pharmacology; D006332:Cardiomegaly / Q000188:drug therapy / Q000201:enzymology*; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D015870:Gene Expression / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000201:enzymology*; D020097:Natriuretic Peptide, Brain; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009638:Norepinephrine / Q000494:pharmacology; D011498:Protein Precursors / Q000235:genetics*; D012333:RNA, Messenger; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology; D018631:ras Proteins / Q000502:physiology
chemical_list: D002147:Calmodulin; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D011498:Protein Precursors; D012333:RNA, Messenger; D013449:Sulfonamides; C063382:prepro-brain natriuretic peptide; D020097:Natriuretic Peptide, Brain; C017967:W 7; D009320:Atrial Natriuretic Factor; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins; D009638:Norepinephrine