Effect of erythropoietin on DNA synthesis, proto-oncogene expression and phospholipase C activity in rat vascular smooth muscle cells.
The administration of recombinant human erythropoietin (rHuEpo) to anemic chronic renal failure patients may be associated with an increase in blood pressure, possibly by direct effects on peripheral blood vessels. The experiments of the present study were designed to explore the hypothesis that rHuEpo might exert mitogenic effects on vascular smooth muscle cells (VSMCs), and that pre-existing hypertension might be a predisposing condition. Cultured aortic VSMCs from spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats were studied for DNA synthesis, phospholipase C activity, and cell growth related proto-oncogene expression in the presence of rHuEpo. In cells from both rat strains, rHuEpo dose-dependently increased DNA synthesis and stimulated phospholipase C activity, as indicated by 3H-thymidine incorporation and inositol phosphate formation, respectively. Exposure of VSMCs to rHuEpo for various periods gradually increased the levels of c-myc and JunB mRNAs and transiently induced c-fos mRNA expression as determined by Northern analysis. The hormone-induced DNA synthesis was markedly enhanced in VSMCs from SHR compared to those from WKY. In contrast, rHuEpo-induced phospholipase C activity and proto-oncogene expression did not differ between the two strains. Taken together, these results suggest that rHuEpo may function as a vascular smooth muscle cell growth promoting factor through activation of the phospholipase C cascade and a modulation of proto-oncogene expression. It could thereby contribute to vascular hypertrophy and arterial hypertension.
Gogusev
J
J
INSERM U 90, Hôpital Necker, Paris, France.
Zhu
D L
DL
Hérembert
T
T
Ammarguellat
F
F
Marche
P
P
Drueke
T
T
D000818:Animals; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis*; D004261:DNA Replication / Q000187:drug effects; D004921:Erythropoietin / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D016758:Genes, jun / Q000187:drug effects*; D016259:Genes, myc / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D011519:Proto-Oncogenes / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011994:Recombinant Proteins / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism*
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011994:Recombinant Proteins; D004921:Erythropoietin; D004247:DNA; D010738:Type C Phospholipases; D013936:Thymidine