Statins inhibited erythropoietin-induced proliferation of rat vascular smooth muscle cells.
Erythropoietin (EPO) directly stimulates the proliferation of vascular smooth muscle cells, and this is believed to be one of the mechanisms of vascular access failure of hemodialysis patients. However, precise mechanisms of the EPO-induced proliferation of vascular smooth muscle cells are not certain. HMG-CoA reductase inhibitors (statins) are primarily used to reduce cholesterol levels, but also exert other effects, including reno-protective effects. We evaluated the effect of several statins with various hydrophilicities on the EPO-induced proliferation of primary cultured rat vascular smooth muscle cells (VSMCs) in vitro. EPO significantly and concentration-dependently increased DNA synthesis as assessed by [³H]thymidine incorporation, cell proliferation as assessed by WST-1 assay, and activation of the p44/42MAPK pathway. Therapeutic doses of statins (pravastatin, simvastatin, atorvastatin and fluvastatin) in patients with hypercholesterolemia almost completely suppressed all of the EPO-induced effects in a concentration-dependent manner. Co-addition of mevalonic acid almost completely reversed the effects of statins. Statin alone did not affect the basal proliferation capacity of the cells. The effects were almost similar among the statins. We concluded that statins inhibited EPO-induced proliferation in rat VSMCs at least partly through their inhibition of HMG-CoA reductase activity. In the future, statins might prove useful for the treatment of EPO-induced hyperplasia of vascular access. Because the statins all showed comparable effects irrespective of their hydrophilicities, these effects might be a class effect.
Kaneda
Tae
T
Department of Clinical Pharmacology, Jichi Medical University, Tochigi, Japan.
Tsuruoka
Shuichi
S
Fujimura
Akio
A
D000818:Animals; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000187:drug effects*; D000068817:Epoetin Alfa; D004921:Erythropoietin / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D057927:Hydrophobic and Hydrophilic Interactions; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006965:Hyperplasia / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009994:Osmolar Concentration; D020011:Protective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020011:Protective Agents; D011994:Recombinant Proteins; D004921:Erythropoietin; D000068817:Epoetin Alfa; D008798:Mevalonic Acid