HMG-CoA reductase inhibition improves endothelial cell function and inhibits smooth muscle cell proliferation in human saphenous veins

OBJECTIVE This study examined effects of 3-hydroxy-3-methylgluraryl CoA (HM G-CoA) reductase inhibitor cerivastatin on human saphenous vein (SV), endot helial cells (EC) and smooth muscle cells (SMC). BACKGROUND Venous bypass graft failure involves EC dysfunction and SMC prol iferation. Substances that improve EC function and inhibit SMC proliferatio n would be of clinical relevance. METHODS Both EC and SMC were isolated from SV. Endothelial nitric oxide syn thase (eNOS) expression and nitric oxide (NO) production were analyzed by i mmunoblotting and porphyrinic microsensor. The SMC proliferation was assaye d by H-3-thymidine incorporation. Protein kinases and cell cycle regulators were analyzed by immunoblotting. RESULTS Cerivastatin (10(-9) to 10(-6) mol/liter) enhanced eNOS protein exp ression and NO release (about two-fold) in EC in response to Ca2+ ionophore (10(-6) mol/liter). This was fully abrogated by the HMG-CoA product mevano late (2 X 10(-4) mol/liter). In SMC, platelet-derived growth factor (5 ng/m l) enhanced H-3-thymidine incorporation (298 +/- 23%, n = 4), activated cyc lin-dependent kinase (Cdk2), phosphorylated Rb and down-regulated p27(Kip1) (but not p21(Cip1)). Cerivastatin reduced the H-3-thymidine incorporation (164 +/- 11%, p < 0.01), inhibited Cdk2 activation and Rb phosphorylation, but did not precent p27(Kip1) down-regulation, nor p42(mapk) and p70(S6K) a ctivation. Mevalonate abrogated the effects of cerivastatin oil Cdk2 and Rb but only partially rescued the H-3 thymidine incorporation (from 164 +/- 1 1% to 211 +/- 13%, n = 4, p < 0.01). CONCLUSIONS In humans, SVEC inhibition of HMG-CoA/mevalonate pathway contri butes to the enhanced eNOS expression and NO release by cerivastatin, where as in SMC, inhibition of this pathway only partially explains cerivastatin- induced cell growth arrest. Inhibition of mechanisms other than p42(mapk) a nd p70(S6K) or Cdk2 are also involved. These effects of cerivastatin could be important in treating venous bypass graft disease. (C) 2000 by the Ameri can College of Cardiology.