(Circulation. 2000;101:1982.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Nitric Oxide Modulates Expression of Cell Cycle Regulatory Proteins
A Cytostatic Strategy for Inhibition of Human Vascular Smooth Muscle Cell Proliferation
From the Cardiovascular Research (F.C.T., H.G., T.F.L.), Physiology Institute, University Zürich-Irchel; Division of Cardiology (F.C.T., T.F.L.), University Hospital, Zürich, Switzerland; Ophthalmology University Hospital (P.M., C.C.), Basel, Switzerland; and Division of Cardiology (E.G.N.), University of Michigan Medical Center, Ann Arbor, Mich.
Correspondence to Thomas F. Lüscher, MD, Cardiology, University Hospital, Rämistrasse 100, 8091 Zürich, Switzerland.
Background—We examined the effect of NO on the proliferation and cell cycle regulation of human aortic vascular smooth muscle cells (VSMCs).
Methods and Results—The NO donor diethylenetriamineNONOate (10-5 to 10-3 mol/L) inhibited proliferation in response to 10% fetal calf serum (FCS) and 100 ng/mL platelet-derived growth factor-BB in a concentration-dependent manner. This effect was not observed with disintegrated diethylenetriamineNONOate or with the parent compound, diethylenetriamine. Adenoviral transfection of endothelial NO synthase (NOS) inhibited proliferation in response to FCS, which was prevented with NG-nitro-L-arginine methyl ester. NOS overexpression did not inhibit proliferation in response to platelet-derived growth factor, although the transfection efficiency and protein expression were similar to those of FCS-stimulated cells. Nitrate release was selectively enhanced from FCS-treated cells, indicating that NOS was activated by FCS only. NO caused G1 cell cycle arrest. Cytotoxicity was determined with trypan blue exclusion, and apoptosis was assessed with DNA fragmentation. Cyclin-dependent kinase 2 expression level, threonine phosphorylation, and kinase activity were inhibited. Cyclin A expression was blunted, whereas cyclin E remained unchanged. p21 expression was induced, and p27 remained unaltered. The effect on cyclin A and p21 started within 6 hours and preceded the changes in cell cycle distribution. Proliferation in response to 10% FCS was barely inhibited with 8-bromo-cGMP (10-3 mol/L) but was blunted with both forskolin and 8-bromo-cAMP. Proliferation in response to 2% FCS was inhibited with 8-bromo-cGMP, but it did not mimic the cell cycle effects of NO.
Conclusions—NO inhibits VSMC proliferation by specifically changing the expression and activity of cell cycle regulatory proteins, which may occur independent of cGMP. Adenoviral overexpression of endothelial NOS represents a cytostatic strategy for gene therapy of vascular disease.
Key Words: endothelium-derived factors • nitric oxide • nitric oxide synthase • platelet-derived factors • gene therapy
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