(Circulation. 1997;96:1899-1905.)
© 1997 American Heart Association, Inc.
Articles |
Adenoviral Constructs Encoding Phosphorylation-Competent Full-length and Truncated Forms of the Human Retinoblastoma Protein Inhibit Myocyte Proliferation and Neointima Formation
From the Division of Cardiovascular Research, Department of Medicine, Tufts University School of Medicine, St. Elizabeth's Medical Center (R.C.S., H.P., L.N.T., K.K., K.W.), Boston, Mass; CANJI, Inc (K.N.W., D.A.), San Diego, Calif; and the Program in Cell, Molecular and Developmental Biology, Sackler School of Biomedical Sciences, Tufts University (H.P., K.W.), Boston, Mass.
Correspondence to Kenneth Walsh, Division of Cardiovascular Research, St Elizabeth's Medical Center, 736 Cambridge St, Boston, MA 02135. E-mail kwalsh{at}opal.tufts.edu
Background The retinoblastoma (Rb) protein is a key cell-cycle regulator that controls entry into the S phase by modulating the activity of the E2F transcription factor. We analyzed the effects of full-length phosphorylation-competent and a mutant truncated form of human Rb for their effects on vascular smooth muscle cell (VSMC) proliferation and neointima formation.
Methods and Results A number of mutant forms, both phosphorylation competent and incompetent, of human Rb protein were evaluated for their ability to inhibit E2F activity. The results of these assays indicated that a phosphorylation competent, amino-terminal–truncated Rb protein (Rb56) was a particularly potent inhibitor of E2F-mediated transcription relative to the full-length Rb construct (Rb110). Adenoviral constructs containing Rb56 or Rb110 expressed their respective Rb forms in VSMCs, as determined by Western immunoblot analysis, and were similar in their abilities to arrest the cell cycle, as determined by assays of 3H-thymidine incorporation and by flow cytometric analyses. When examined for their effect on neointima formation after balloon injury of the rat carotid artery, both full-length and truncated forms of Rb inhibited formation of this VSMC-derived lesion.
Conclusions These analyses revealed that the maintenance of high levels of phosphorylation-competent human Rb, either full-length or truncated forms, in VSMCs is an effective method of modulating the extent of intimal hyperplasia that occurs after balloon-induced vascular injury.
Key Words: angioplasty • genes • carotid arteries • muscle, smooth • stenosis
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