title: Cell-type- and cell-cycle-specific anti-mitogenesis by cicaprost.
abstract: Stents eluting anti-proliferative drugs limit restenosis, but drugs commonly used to date are relatively non-specific cytostatic agents which inhibit proliferation of intimal endothelial cells as well as medial smooth muscle cells and may thereby contribute to the clinical complications associated with angioplasty. In an effort to identify a more specific anti-proliferative agent, we compared the effects of rapamycin to those of cicaprost, a mimetic of the naturally occurring anti-mitogen, PGI(2). Rapamycin and cicaprost were both strongly anti-mitogenic in vascular smooth muscle cells (VSMCs). But unlike rapamycin, cicaprost did not inhibit mitogenesis in aortic endothelial cells even when used at concentrations >10-fold higher than its ED(50) for VSMCs. Similarly, both rapamycin and cicaprost have been reported to regulate levels of the cdk inhibitor, p27(kip1). But rapamycin remained anti-mitogenic in p27(kip1)-null VSMCs whereas the anti-mitogenic effect of cicaprost was completely dependent on p27(kip1). We conclude that stable PGI(2) mimetics may be highly specific inhibitors of p27(kip1)-dependent VSMC proliferation after vascular injury.
authors.affiliation: Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6084, United States. pcastagn@mail.med.upenn.edu
authors.forename: Paola
authors.initials: P
authors.lastname: Castagnino
authors.forename: Devashish
authors.initials: D
authors.lastname: Kothapalli
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Hawthorne
authors.forename: Tina
authors.initials: T
authors.lastname: Xu
authors.forename: Richard K
authors.initials: RK
authors.lastname: Assoian
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008938:Mitosis / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology
chemical_list: D018797:Cell Cycle Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011464:Epoprostenol; C043867:cicaprost; D020123:Sirolimus
references.citation: Prostaglandins. 1991 Feb;41(2):97-110
references.pmid: 1708156
references.citation: Annu Rev Med. 2004;55:169-78
references.pmid: 14746515
references.citation: J Am Coll Cardiol. 2006 Dec 19;48(12):2584-91
references.pmid: 17174201
references.citation: Prostaglandins. 1994 Feb;47(2):151-68
references.pmid: 8016385
references.citation: Semin Interv Cardiol. 1996 Sep;1(3):181-4
references.pmid: 9552509
references.citation: Genes Dev. 1999 Jun 15;13(12):1501-12
references.pmid: 10385618
references.citation: Methods Enzymol. 2007;426:155-75
references.pmid: 17697884
references.citation: Lancet. 2004 Oct 23-29;364(9444):1519-21
references.pmid: 15500897
references.citation: Atherosclerosis. 2006 Dec;189(2):288-96
references.pmid: 16455087
references.citation: N Engl J Med. 2003 Oct 2;349(14):1307-9
references.pmid: 14523135
references.citation: Mol Cell Biol. 1996 Dec;16(12):6744-51
references.pmid: 8943329
references.citation: Nat Rev Mol Cell Biol. 2009 May;10(5):307-18
references.pmid: 19339977
references.citation: Nat Med. 1997 Aug;3(8):900-3
references.pmid: 9256282
references.citation: Prostaglandins Other Lipid Mediat. 2007 Jan;82(1-4):109-18
references.pmid: 17164138
references.citation: Circulation. 2001 Aug 21;104(8):852-5
references.pmid: 11514367
references.citation: J Cardiovasc Pharmacol. 2006 Dec;48(6):286-92
references.pmid: 17204907
references.citation: Cardiovasc Res. 2001 Dec;52(3):500-8
references.pmid: 11738067
references.citation: Science. 1995 Jan 27;267(5197):518-22
references.pmid: 7824950
references.citation: J Biol Chem. 2004 Jul 9;279(28):29109-13
references.pmid: 15126498
references.citation: Science. 2002 Apr 19;296(5567):539-41
references.pmid: 11964481
references.citation: Cardiovasc Res. 2005 Dec 1;68(3):483-92
references.pmid: 16111664
references.citation: Mol Pharmacol. 2006 Nov;70(5):1700-7
references.pmid: 16885208
references.citation: Physiol Rev. 1999 Oct;79(4):1193-226
references.pmid: 10508233
references.citation: Mol Pharmacol. 2003 Aug;64(2):249-58
references.pmid: 12869629
references.citation: Circulation. 1997 Sep 16;96(6):1717-9
references.pmid: 9323050