High glucose blocks the effects of estradiol on human vascular cell growth: differential interaction with estradiol and raloxifene.
Because diabetic women appear not to be protected by estrogen in terms of propensity to cardiovascular disease, we tested the possibility that chronic hyperglycemia modulates the effects of E(2) on vascular cell growth in vitro. Human endothelial cells (E304) and vascular smooth muscle cells (VSMC) were grown in normal glucose (5.5 mmol/l), high glucose (22 mmol/l) or high manitol (22 nmol/l; an osmotic control) for 7 days. In endothelial cells glucose per se stimulated DNA synthesis. However E(2)- (but not RAL-) stimulated [3H] thymidine incorporation was attenuated in the presence of high glucose. In parallel, E(2)-dependent MAP-kinase-kinase activity was blocked in the presence of high glucose. High glucose increased basal creatine kinase (CK) specific activity, but E(2)-stimulated CK was not significantly impaired in the presence of high glucose. In VSMC, high glucose prevented the inhibitory effect of high E(2) (but not of high RAL) concentrations on DNA synthesis. High glucose also prevented E(2)-induced MAP-kinase-kinase activity. In contrast, while high glucose augmented basal CK, the relative E(2)-induced changes were roughly equal in normal and high high glucose media. Hence, high glucose blocks several effects of E(2) on vascular cell growth, which are mediated, in part, via the MAP-kinase system and are likely contributors to E(2)'s anti-atherosclerotic properties. Since RAL's estrogen-mimetic effects on human vascular cell growth were independent of MAP-kinase activation and were not affected by hyperglycemia, the potential use of RAL to circumvent the loss of estrogen function induced by hyperglycemia and diabetes in the human vasculature should be further explored.
Somjen
Dalia
D
Institute of Endocrinology, Metabolism and Hypertension, Tel Aviv Sourasky Medical Center, and Sackler Faculty of Medicine Tel Aviv University, 6 Weizman Street, Tel Aviv 64239, Rehovot, Israel.
Paller
Channing J
CJ
Gayer
Batya
B
Kohen
Fortune
F
Knoll
Esther
E
Stern
Naftali
N
D002460:Cell Line; D002478:Cells, Cultured; D003402:Creatine Kinase / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development* / Q000378:metabolism*; D004789:Enzyme Activation; D004958:Estradiol / Q000378:metabolism*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008353:Mannitol / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development* / Q000378:metabolism*; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D013936:Thymidine / Q000493:pharmacokinetics; D013997:Time Factors; D014316:Tritium; D014469:Umbilical Arteries / Q000166:cytology; D014471:Umbilical Veins / Q000166:cytology
D004965:Estrogen Antagonists; D014316:Tritium; D008353:Mannitol; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D020929:Mitogen-Activated Protein Kinase Kinases; D003402:Creatine Kinase; D005947:Glucose; D013936:Thymidine