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. 1993 Apr;91(4):1469–1480. doi: 10.1172/JCI116352

Proliferative activity in peripheral and coronary atherosclerotic plaque among patients undergoing percutaneous revascularization.

J G Pickering 1, L Weir 1, J Jekanowski 1, M A Kearney 1, J M Isner 1
PMCID: PMC288122  PMID: 8097207

Abstract

We evaluated the proliferative activity of human atherosclerotic lesions associated with active symptoms of ischemia, by assessing the expression of the proliferating cell nuclear antigen (PCNA). We confirmed in vitro that PCNA, an essential component of the DNA synthesis machinery, is selectively expressed in proliferating human vascular smooth muscle cells. 37 atherosclerotic lesions (18 primary and 19 restenotic) retrieved by directional atherectomy from either coronary or peripheral arteries were then studied for the expression of PCNA, using in situ hybridization or immunohistochemistry. Among plaques studied by in situ hybridization, 7 out of 11 primary and 11 out of 11 restenotic lesions contained PCNA-positive cells. The mean rate of proliferation (percent of PCNA-positive cells) was 7.2 +/- 10.8% in primary lesions and 20.6 +/- 18.2% in restenotic lesions (P < 0.05). Among specimens studied by immunohistochemistry, five out of seven primary and eight out of eight restenotic lesions contained proliferating cells. The mean rate of proliferation was again higher in the restenotic (15.2 +/- 13.6%) than primary (3.6 +/- 3.5%) lesions (P < 0.05). Proliferating cells were detected as late as 1 yr after angioplasty. We conclude that cellular proliferation is a feature of atherosclerotic lesions which are associated with symptoms of ischemia, but that it is more prominent in restenosis compared to primary lesions. These findings have implications for therapies aimed at limiting lesion growth, particularly after percutaneous revascularization.

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Selected References

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  1. Almendral J. M., Huebsch D., Blundell P. A., Macdonald-Bravo H., Bravo R. Cloning and sequence of the human nuclear protein cyclin: homology with DNA-binding proteins. Proc Natl Acad Sci U S A. 1987 Mar;84(6):1575–1579. doi: 10.1073/pnas.84.6.1575. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ambrose J. A., Winters S. L., Stern A., Eng A., Teichholz L. E., Gorlin R., Fuster V. Angiographic morphology and the pathogenesis of unstable angina pectoris. J Am Coll Cardiol. 1985 Mar;5(3):609–616. doi: 10.1016/s0735-1097(85)80384-3. [DOI] [PubMed] [Google Scholar]
  3. Benditt E. P., Benditt J. M. Evidence for a monoclonal origin of human atherosclerotic plaques. Proc Natl Acad Sci U S A. 1973 Jun;70(6):1753–1756. doi: 10.1073/pnas.70.6.1753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bravo R., Celis J. E. A search for differential polypeptide synthesis throughout the cell cycle of HeLa cells. J Cell Biol. 1980 Mar;84(3):795–802. doi: 10.1083/jcb.84.3.795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bravo R., Frank R., Blundell P. A., Macdonald-Bravo H. Cyclin/PCNA is the auxiliary protein of DNA polymerase-delta. Nature. 1987 Apr 2;326(6112):515–517. doi: 10.1038/326515a0. [DOI] [PubMed] [Google Scholar]
  6. Bravo R., Macdonald-Bravo H. Existence of two populations of cyclin/proliferating cell nuclear antigen during the cell cycle: association with DNA replication sites. J Cell Biol. 1987 Oct;105(4):1549–1554. doi: 10.1083/jcb.105.4.1549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bravo R. Synthesis of the nuclear protein cyclin (PCNA) and its relationship with DNA replication. Exp Cell Res. 1986 Apr;163(2):287–293. doi: 10.1016/0014-4827(86)90059-5. [DOI] [PubMed] [Google Scholar]
  8. Dartsch P. C., Voisard R., Bauriedel G., Höfling B., Betz E. Growth characteristics and cytoskeletal organization of cultured smooth muscle cells from human primary stenosing and restenosing lesions. Arteriosclerosis. 1990 Jan-Feb;10(1):62–75. doi: 10.1161/01.atv.10.1.62. [DOI] [PubMed] [Google Scholar]
  9. Fuster V., Badimon L., Badimon J. J., Chesebro J. H. The pathogenesis of coronary artery disease and the acute coronary syndromes (1). N Engl J Med. 1992 Jan 23;326(4):242–250. doi: 10.1056/NEJM199201233260406. [DOI] [PubMed] [Google Scholar]
  10. Galand P., Degraef C. Cyclin/PCNA immunostaining as an alternative to tritiated thymidine pulse labelling for marking S phase cells in paraffin sections from animal and human tissues. Cell Tissue Kinet. 1989 Sep;22(5):383–392. doi: 10.1111/j.1365-2184.1989.tb00223.x. [DOI] [PubMed] [Google Scholar]
  11. Garcia R. L., Coltrera M. D., Gown A. M. Analysis of proliferative grade using anti-PCNA/cyclin monoclonal antibodies in fixed, embedded tissues. Comparison with flow cytometric analysis. Am J Pathol. 1989 Apr;134(4):733–739. [PMC free article] [PubMed] [Google Scholar]
  12. Garratt K. N., Edwards W. D., Kaufmann U. P., Vlietstra R. E., Holmes D. R., Jr Differential histopathology of primary atherosclerotic and restenotic lesions in coronary arteries and saphenous vein bypass grafts: analysis of tissue obtained from 73 patients by directional atherectomy. J Am Coll Cardiol. 1991 Feb;17(2):442–448. doi: 10.1016/s0735-1097(10)80113-5. [DOI] [PubMed] [Google Scholar]
  13. Gordon D., Reidy M. A., Benditt E. P., Schwartz S. M. Cell proliferation in human coronary arteries. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4600–4604. doi: 10.1073/pnas.87.12.4600. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. HAUST M. D., MORE R. H., MOVAT H. Z. The role of smooth muscle cells in the fibrogenesis of arteriosclerosis. Am J Pathol. 1960 Oct;37:377–389. [PMC free article] [PubMed] [Google Scholar]
  15. Hall P. A., Levison D. A., Woods A. L., Yu C. C., Kellock D. B., Watkins J. A., Barnes D. M., Gillett C. E., Camplejohn R., Dover R. Proliferating cell nuclear antigen (PCNA) immunolocalization in paraffin sections: an index of cell proliferation with evidence of deregulated expression in some neoplasms. J Pathol. 1990 Dec;162(4):285–294. doi: 10.1002/path.1711620403. [DOI] [PubMed] [Google Scholar]
  16. Hanke H., Strohschneider T., Oberhoff M., Betz E., Karsch K. R. Time course of smooth muscle cell proliferation in the intima and media of arteries following experimental angioplasty. Circ Res. 1990 Sep;67(3):651–659. doi: 10.1161/01.res.67.3.651. [DOI] [PubMed] [Google Scholar]
  17. Hermans W. R., Rensing B. J., Strauss B. H., Serruys P. W. Prevention of restenosis after percutaneous transluminal coronary angioplasty: the search for a "magic bullet". Am Heart J. 1991 Jul;122(1 Pt 1):171–187. doi: 10.1016/0002-8703(91)90775-d. [DOI] [PubMed] [Google Scholar]
  18. Ip J. H., Fuster V., Badimon L., Badimon J., Taubman M. B., Chesebro J. H. Syndromes of accelerated atherosclerosis: role of vascular injury and smooth muscle cell proliferation. J Am Coll Cardiol. 1990 Jun;15(7):1667–1687. doi: 10.1016/0735-1097(90)92845-s. [DOI] [PubMed] [Google Scholar]
  19. Jaskulski D., Gatti C., Travali S., Calabretta B., Baserga R. Regulation of the proliferating cell nuclear antigen cyclin and thymidine kinase mRNA levels by growth factors. J Biol Chem. 1988 Jul 25;263(21):10175–10179. [PubMed] [Google Scholar]
  20. Jaskulski D., deRiel J. K., Mercer W. E., Calabretta B., Baserga R. Inhibition of cellular proliferation by antisense oligodeoxynucleotides to PCNA cyclin. Science. 1988 Jun 10;240(4858):1544–1546. doi: 10.1126/science.2897717. [DOI] [PubMed] [Google Scholar]
  21. Johnson D. E., Hinohara T., Selmon M. R., Braden L. J., Simpson J. B. Primary peripheral arterial stenoses and restenoses excised by transluminal atherectomy: a histopathologic study. J Am Coll Cardiol. 1990 Feb;15(2):419–425. doi: 10.1016/s0735-1097(10)80071-3. [DOI] [PubMed] [Google Scholar]
  22. Kamel O. W., Franklin W. A., Ringus J. C., Meyer J. S. Thymidine labeling index and Ki-67 growth fraction in lesions of the breast. Am J Pathol. 1989 Jan;134(1):107–113. [PMC free article] [PubMed] [Google Scholar]
  23. Kawakita N., Seki S., Sakaguchi H., Yanai A., Kuroki T., Mizoguchi Y., Kobayashi K., Monna T. Analysis of proliferating hepatocytes using a monoclonal antibody against proliferating cell nuclear antigen/cyclin in embedded tissues from various liver diseases fixed in formaldehyde. Am J Pathol. 1992 Feb;140(2):513–520. [PMC free article] [PubMed] [Google Scholar]
  24. Leclerc G., Isner J. M., Kearney M., Simons M., Safian R. D., Baim D. S., Weir L. Evidence implicating nonmuscle myosin in restenosis. Use of in situ hybridization to analyze human vascular lesions obtained by directional atherectomy. Circulation. 1992 Feb;85(2):543–553. doi: 10.1161/01.cir.85.2.543. [DOI] [PubMed] [Google Scholar]
  25. Levin D. C., Fallon J. T. Significance of the angiographic morphology of localized coronary stenoses: histopathologic correlations. Circulation. 1982 Aug;66(2):316–320. doi: 10.1161/01.cir.66.2.316. [DOI] [PubMed] [Google Scholar]
  26. Mecley M., Rosenfield K., Kaufman J., Langevin R. E., Jr, Razvi S., Isner J. M. Atherosclerotic plaque hemorrhage and rupture associated with crescendo claudication. Ann Intern Med. 1992 Oct 15;117(8):663–666. doi: 10.7326/0003-4819-117-8-663. [DOI] [PubMed] [Google Scholar]
  27. Nobuyoshi M., Kimura T., Ohishi H., Horiuchi H., Nosaka H., Hamasaki N., Yokoi H., Kim K. Restenosis after percutaneous transluminal coronary angioplasty: pathologic observations in 20 patients. J Am Coll Cardiol. 1991 Feb;17(2):433–439. doi: 10.1016/s0735-1097(10)80111-1. [DOI] [PubMed] [Google Scholar]
  28. Pickering J. G., Weir L., Rosenfield K., Stetz J., Jekanowski J., Isner J. M. Smooth muscle cell outgrowth from human atherosclerotic plaque: implications for the assessment of lesion biology. J Am Coll Cardiol. 1992 Nov 15;20(6):1430–1439. doi: 10.1016/0735-1097(92)90259-p. [DOI] [PubMed] [Google Scholar]
  29. Prelich G., Tan C. K., Kostura M., Mathews M. B., So A. G., Downey K. M., Stillman B. Functional identity of proliferating cell nuclear antigen and a DNA polymerase-delta auxiliary protein. Nature. 1987 Apr 2;326(6112):517–520. doi: 10.1038/326517a0. [DOI] [PubMed] [Google Scholar]
  30. Richardson P. D., Davies M. J., Born G. V. Influence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaques. Lancet. 1989 Oct 21;2(8669):941–944. doi: 10.1016/s0140-6736(89)90953-7. [DOI] [PubMed] [Google Scholar]
  31. Ross R., Glomset J., Kariya B., Harker L. A platelet-dependent serum factor that stimulates the proliferation of arterial smooth muscle cells in vitro. Proc Natl Acad Sci U S A. 1974 Apr;71(4):1207–1210. doi: 10.1073/pnas.71.4.1207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Ross R., Masuda J., Raines E. W. Cellular interactions, growth factors, and smooth muscle proliferation in atherogenesis. Ann N Y Acad Sci. 1990;598:102–112. doi: 10.1111/j.1749-6632.1990.tb42282.x. [DOI] [PubMed] [Google Scholar]
  33. Ross R. The pathogenesis of atherosclerosis--an update. N Engl J Med. 1986 Feb 20;314(8):488–500. doi: 10.1056/NEJM198602203140806. [DOI] [PubMed] [Google Scholar]
  34. Ross R., Wight T. N., Strandness E., Thiele B. Human atherosclerosis. I. Cell constitution and characteristics of advanced lesions of the superficial femoral artery. Am J Pathol. 1984 Jan;114(1):79–93. [PMC free article] [PubMed] [Google Scholar]
  35. Serruys P. W., Luijten H. E., Beatt K. J., Geuskens R., de Feyter P. J., van den Brand M., Reiber J. H., ten Katen H. J., van Es G. A., Hugenholtz P. G. Incidence of restenosis after successful coronary angioplasty: a time-related phenomenon. A quantitative angiographic study in 342 consecutive patients at 1, 2, 3, and 4 months. Circulation. 1988 Feb;77(2):361–371. doi: 10.1161/01.cir.77.2.361. [DOI] [PubMed] [Google Scholar]
  36. Sherman C. T., Litvack F., Grundfest W., Lee M., Hickey A., Chaux A., Kass R., Blanche C., Matloff J., Morgenstern L. Coronary angioscopy in patients with unstable angina pectoris. N Engl J Med. 1986 Oct 9;315(15):913–919. doi: 10.1056/NEJM198610093151501. [DOI] [PubMed] [Google Scholar]
  37. Spagnoli L. G., Villaschi S., Neri L., Palmieri G., Taurino M., Faraglia V., Fiorani P. Autoradiographic studies of the smooth muscle cells in human arteries. Paroi Arterielle. 1981;7(3):107–112. [PubMed] [Google Scholar]
  38. Suzuka I., Daidoji H., Matsuoka M., Kadowaki K., Takasaki Y., Nakane P. K., Moriuchi T. Gene for proliferating-cell nuclear antigen (DNA polymerase delta auxiliary protein) is present in both mammalian and higher plant genomes. Proc Natl Acad Sci U S A. 1989 May;86(9):3189–3193. doi: 10.1073/pnas.86.9.3189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Ueda M., Becker A. E., Tsukada T., Numano F., Fujimoto T. Fibrocellular tissue response after percutaneous transluminal coronary angioplasty. An immunocytochemical analysis of the cellular composition. Circulation. 1991 Apr;83(4):1327–1332. doi: 10.1161/01.cir.83.4.1327. [DOI] [PubMed] [Google Scholar]
  40. Villaschi S., Spagnoli L. G. Autoradiographic and ultrastructural studies on the human fibro-atheromatous plaque. Atherosclerosis. 1983 Jul;48(1):95–100. doi: 10.1016/0021-9150(83)90020-5. [DOI] [PubMed] [Google Scholar]
  41. Waseem N. H., Lane D. P. Monoclonal antibody analysis of the proliferating cell nuclear antigen (PCNA). Structural conservation and the detection of a nucleolar form. J Cell Sci. 1990 May;96(Pt 1):121–129. doi: 10.1242/jcs.96.1.121. [DOI] [PubMed] [Google Scholar]

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