Donate Help Contact The AHA Sign In Home
American Heart Association
Circulation
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Circulation. 1996;94:2694-2695

This Article
Right arrow Extract Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Haber, E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Haber, E.

(Circulation. 1996;94:2694-2695.)
© 1996 American Heart Association, Inc.

Articles

Can a Viral Serine Proteinase Inhibitor Prevent Postangioplasty Restenosis?

Edgar Haber, MD

the Center for the Prevention of Cardiovascular Disease, Harvard School of Public Health and Harvard Medical School, Boston, Mass.

Correspondence to Dr Edgar Haber, Harvard School of Public Health, 655 Huntington Ave, Boston, MA 02115-6018. E-mail haber@cvlab.harvard.edu.


Key Words: Editorials • viruses • immune system • enzymes • stenosis


*    Introduction
up arrowTop
 *Introduction
down arrowReferences
 
The sudden disappearance of the rabbit overpopulation in Australia was caused by the rapid spread of infection by the myxoma virus. Because it is transmitted venereally, the virus takes full advantage of the fabled promiscuity of its host. More importantly, however, it promotes secretion of a number of proteins that defeat the rabbit's cellular and immune responses to infection, thereby allowing the virus to take unopposed hold of its victim's tissues.

In this issue, Lucas et al1 present evidence that the serine proteinase inhibitor SERP-1, which is encoded by the myxoma virus2 and is essential to its ability to infect, ameliorates atherosclerosis in a rabbit model. Long ascribed to an inflammatory response, atherosclerosis begins with the transepithelial migration of monocytes and T cells from the blood to the neointimal space.3 Some of these monocytes then become macrophages that appear on histological examination as lipid-laden foam cells, which predominate in the earliest mass lesion of atherosclerosis, the fatty streak.3 The other clinically important forms of arteriosclerosis—postangioplasty restenosis, vein bypass graft failure, and transplant arteriosclerosis—can also begin as inflammatory lesions. All forms of arteriosclerosis are ultimately sustained by more complex processes that also involve migration of smooth muscle cells.

Lucas et al1 obtained SERP-1 from tissue culture cells that had been infected with a recombinant vaccinia virus that also encoded SERP-1. They also obtained a mutant form of SERP-1 that lacked proteinase inhibitor activity, an important control. When native SERP-1 was infused locally (through a perforated catheter) at low doses or systemically at high doses, there was a highly significant reduction in plaque area in balloon-injured rabbit arteries. And in early and late lesions, the number of mononuclear leukocytes, T cells, and monocytes was reduced, clearly indicating a marked effect on the vascular inflammatory response. However, SERP-1 had no effect on the number of smooth muscle cells in lesions. The mutated form of SERP-1 lacked any activity, indicating that the inhibition of serine proteinase activity was the key to the efficacy of SERP-1.

These findings are not surprising in light of the established role of serine proteinases such as urokinase-type plasminogen activator and plasmin in promoting cellular migration by lysing components of the extracellular matrix. The activity of some serine proteinases is moderated by plasminogen activator inhibitor-1, an intrinsic serine proteinase inhibitor. When the gene coding for plasminogen activator inhibitor-1 is deleted in the mouse, the progress of the arteriosclerotic process is accelerated.4 This observation indicates that serine proteinase inhibition is an essential moderator of cell migration and, by extension, that further inhibition by administration of an inhibitor such as SERP-1 should inhibit cell migration further and thereby moderate those aspects of arteriosclerosis that depend on cellular migration.

Cytokine receptors, the cell-cell interaction, the cell-matrix interaction, integrins, the redox state, intracellular signaling pathways (including tyrosine kinases), and transcription factors have all been studied as selective interventions for arteriosclerosis and its variants, as has general inhibition of cellular proliferation as a nonselective intervention.5 In rodent models, attempts to block arteriosclerotic pathways at each level of cellular activation, from the cell membrane receptor to the nucleus, have shown significant effects. Yet the translation of these observations to clinical therapy has been slow. The only controlled prospective clinical trial so far has shown that c7E3 (a chimeric anti–GP IIb/IIIa integrin antibody specific for the fibrinogen receptor on platelets) significantly reduced the incidence of major ischemic events and elective revascularization at 6 months when infused at the time of angioplasty.6 Although the mechanism for these effects (observed 6 months after administration of a drug for only a few hours) has not been clarified, there is speculation that integrins on the surface of endothelial cells and platelets were blocked and consequently transepithelial inflammatory cell migration was inhibited. The net result obtained with c7E3 is similar to that obtained with SERP-1, even though the mechanism may be different. Because no other potential molecular interventions have come this far5 and because studies of SERP-1 are at an early stage, it is difficult to determine whether serine proteinase inhibition represents a useful therapeutic avenue.

Lucas et al1 relate their most interesting findings to the problem of restenosis after angioplasty. In my opinion, however, their observations speak more to another form of arteriosclerosis, chronic atherosclerosis. Lucas et al appear to base their appreciation of the pathophysiology of postangioplasty restenosis on well-studied rat and rabbit models. For example, after endothelial denudation and balloon dilation of the normal rat carotid artery, smooth muscle cells in the tunica media of the artery proliferate and then migrate to the intimal space. They then undergo another cycle of proliferation that creates a partially obstructive lesion composed largely of smooth muscle cells.3 In the rabbit model studied by Lucas et al,1 induction of atherosclerosis requires cholesterol and lipid overfeeding, followed by angioplasty of the aorta. From the histological figures presented in their paper, it is clear that the rabbit intimal lesion contains leukocytes, foam cells, and smooth muscle cells. In this setting, an agent that inhibited cell migration would certainly have an effect on lesions dependent on the influx of leukocytes. In humans, however, there is scant evidence for any sort of cellular infiltration or proliferation after angioplasty. O'Brien et al7 studied 118 primary and 100 restenotic human coronary atherectomy specimens with an immunohistochemical stain for proliferating cell nuclear antigen (PCNA), a marker of cell division. Eighty-two percent of the primary specimens and 74% of the restenotic specimens showed no evidence of PCNA labeling, indicating no proliferation, whereas the remaining specimens showed only a modest number of PCNA-positive cells per slide. Although some contrary evidence has been published,8 the weight of opinion9 favors mechanisms other than cell infiltration or proliferation as the primary cause of postangioplasty restenosis in humans. Indeed, intravascular ultrasound studies have failed to show a major increase in plaque area with restenosis.10 11 In an extensive analysis of this problem, Schwartz et al9 concluded that postangioplasty restenosis may reflect simple healing of the dilated wall (without any further increase in mass) or addition of a small amount of mass to replace what was lost during angioplasty. A better case for cellular hyperplasia has been made in the setting of restenosis after stenting.12

But postangioplasty restenosis should not be the only target for serine proteinase inhibitor therapy. Chronic atherosclerosis begins in humans as a fatty streak that resembles the lesion obtained in the rabbit model used by Lucas et al.1 Its pathogenesis depends on macrophage infiltration, which could well be inhibited by a SERP-1–like molecule that was suitable for long-term administration with a minimum of toxicity. SERP-1 itself is not likely to be useful in this context, because long-term administration of a viral protein would probably result in the formation of neutralizing antibodies. A somewhat unsettling observation made by Lucas et al is that smooth muscle cell proliferation is unimpeded by SERP-1. Transplant arteriosclerosis, the major cause of death after the first year of cardiac transplantation,13 is characterized largely by smooth muscle cell proliferation,14 yet as Shi et al15 have shown recently, the presence of CD4+ T cells, B cells, and macrophages is required before initiation of smooth muscle cell migration and proliferation. Thus, if SERP-1 aborted the inflammatory response, it might also prevent formation of a smooth muscle cell lesion.

The rabbit myxoma virus is a fascinating tool for illuminating the complexity of the atherosclerotic process. Although I doubt that SERP-1 will lead to a drug for the prevention of postangioplasty restenosis, the experiments of Lucas et al1 have uncovered an important avenue for exploring mechanisms that inhibit the formation of other arterial lesions.


*    Footnotes
 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.


*    References
up arrowTop
 up arrowIntroduction
 *References
 

  1. Lucas A, Liu L, Macen J, Nash P, Dai E, Stewart M, Yan W, Graham K, Etches W, Boshkov L, Nation PN, Humen D, Hobman ML, McFadden G. A virus-encoded serine proteinase inhibitor, SERP-1, inhibits atherosclerotic plaque development following balloon angioplasty. Circulation.. 1996;94:2890-2900.[Abstract/Free Full Text]
  2. Macen JL, Upton C, Nation N, McFadden G. SERP1, a serine proteinase inhibitor encoded by myxoma virus, is a secreted glycoprotein that interferes with inflammation. Virology.. 1993;195:348-363.[Medline] [Order article via Infotrieve]
  3. Ross R. Cell biology of atherosclerosis. Annu Rev Physiol.. 1995;57:791-804.[Medline] [Order article via Infotrieve]
  4. Carmeliet P, Collen D. Gene targeting and gene transfer studies of the plasminogen/plasmin system: implications in thrombosis, hemostasis, neointima formation, and atherosclerosis. FASEB J.. 1995;9:934-938.[Abstract]
  5. Gibbons GH, Dzau VJ. Molecular therapies for vascular diseases. Science.. 1996;272:689-693.[Abstract]
  6. Topol EJ, Califf RM, Weisman HF, Ellis SG, Tcheng JE, Worley S, Ivanhoe R, George BS, Fintel D, Weston M, Sigmon K, Anderson KM, Lee KL, Willerson JT, for the EPIC Investigators. Randomised trial of coronary intervention with antibody against platelet IIb/IIIa integrin for reduction of clinical restenosis: results at six months. Lancet.. 1994;343:881-886.[Medline] [Order article via Infotrieve]
  7. O'Brien ER, Alpers CE, Stewart DK, Ferguson M, Tran N, Gordon D, Benditt EP, Hinohara T, Simpson JB, Schwartz SM. Proliferation in primary and restenotic coronary atherectomy tissue: implications for antiproliferative therapy. Circ Res.. 1993;73:223-231.[Abstract/Free Full Text]
  8. Pickering JG, Weir L, Jekanowski J, Kearney MA, Isner JM. Proliferative activity in peripheral and coronary atherosclerotic plaque among patients undergoing percutaneous revascularization. J Clin Invest.. 1993;91:1469-1480.
  9. Schwartz SM, Reidy MA, O'Brien ER. Assessment of factors important in atherosclerotic occlusion and restenosis. Thromb Haemost.. 1995;74:541-551.[Medline] [Order article via Infotrieve]
  10. Mintz GS, Pichard AD, Kent KM, Satler LF, Popma JJ, Leon MB. Intravascular ultrasound comparison of restenotic and de novo coronary artery narrowings. Am J Cardiol.. 1994;74:1278-1280.[Medline] [Order article via Infotrieve]
  11. Mintz GS, Popma JJ, Pichard AD, Kent KM, Salter LF, Chuang YC, Griffin J, Leon MB. Intravascular ultrasound predictors of restenosis after percutaneous transcatheter coronary revascularization. J Am Coll Cardiol.. 1996;27:1678-1687.[Abstract]
  12. Gordon PC, Gibson CM, Cohen DJ, Carrozza JP, Kuntz RE, Baim DS. Mechanisms of restenosis and redilation within coronary stents: quantitative angiographic assessment. J Am Coll Cardiol.. 1993;21:1166-1174.[Abstract]
  13. Sharples LD, Caine N, Mullins P, Scott JP, Solis E, English TA, Large SR, Schofield PM, Wallwork J. Risk factor analysis for the major hazards following heart transplantation: rejection, infection, and coronary occlusive disease. Transplantation.. 1991;52:244-252.[Medline] [Order article via Infotrieve]
  14. Billingham ME. Cardiac transplant atherosclerosis. Transplant Proc. 1987;19(suppl 5):19-25.
  15. Shi C, Lee WS, He Q, Zhang D, Fletcher DL Jr, Newell JB, Haber E. Immunologic basis of transplant-associated arteriosclerosis. Proc Natl Acad Sci U S A.. 1996;93:4051-4056.[Abstract/Free Full Text]




This Article
Right arrow Extract Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Haber, E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Haber, E.

Circulation Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search
Copyright © 1996 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited.