ANIMAL AND IN VITRO MODELS IN HUMAN DISEASES
Different inflammatory response and oxidative stress in neointimal hyperplasia after balloon angioplasty and stent implantation in cholesterol-fed rabbits

https://doi.org/10.1016/j.prp.2005.12.011Get rights and content

Abstract

Inflammatory responses appear to play an important role in the occurrence of restenosis following coronary intervention. However, the contribution of C-reactive protein (CRP) and oxidative stress to restenosis after balloon angioplasty and stent implantation remains unclear. The aim of this study was to examine this issue using hyperlipidemic rabbits. Rabbits were divided into two groups; they were fed with a 0.5% cholesterol diet and with a mixed 0.5% cholesterol and 0.5% probucol diet. Each group of rabbits underwent balloon injury and stent implantation in right and left iliac arteries, respectively. Eight weeks after the intervention, we examined luminal stenosis, neointimal hyperplasia, immunoreactivity for macrophage, CRP and oxidized phosphatidylcholine (oxPC), and also the expression of CRP mRNA. The degrees of neointimal hyperplasia and immunopositive areas (%) for macrophage, CRP, and oxPC in the neointima were significantly higher after stent implantation than after balloon injury, but CRP mRNA was undetectable in either artery. Anti-oxidant probucol reduced angiographic stenosis, neointimal hyperplasia, and macrophage- and oxPC-positive areas much more significantly after stenting. The results demonstrate that the inflammatory response to the development of neointimal hyperplasia differs after balloon injury and stent implantation and that CRP deposition and oxidative stress might be involved more significantly in neointimal development after stent implantation.

Introduction

Restenosis after percutaneous coronary interventions (PCI) is an important clinical issue because large numbers of coronary interventions are required, and their indication is expanding. Although the use of drug-eluting stent dramatically reduced the incidence of restenosis, restenosis still remains a crucial problem [4]. Restenosis after balloon angioplasty is considered to arise through a combination of inadequate or deleterious arterial remodeling and neointimal hyperplasia, whereas in-stent restenosis arises primarily from neointimal hyperplasia [28], [31]. Increasing evidence from both clinical and animal studies indicates that inflammation plays a pivotal role in restenosis after both types of intervention [12].

C-reactive protein (CRP) is an acute phase protein that can serve as a marker of inflammation. In prospective epidemiologic studies, plasma levels of CRP predict future cardiovascular events [32], and recent clinical studies indicate that this protein is also a predictor of restenosis after PCI [2], [6]. We have previously reported that positive immunostaining for CRP in initial culprit lesions could predict the outcome of directional coronary atherectomy (DCA) [17], and CRP was more involved in the pathogenesis of in-stent restenosis than in that of restenosis after DCA [21]. In addition, CRP has a pro-oxidative effect [23], and oxidation is implicated in atherogenesis and restenosis after PCI [3], [38]. These lines of evidence suggest that CRP and oxidized lipoprotein are directly involved in the development of restenotic lesions. However, expression and localization of these molecules in restenotic lesions has not been well examined.

The present study investigated the synthesis of CRP, the localization of CRP and oxidized lipoprotein in neointimal hyperplasia after balloon injury and stent implantation in hyperlipidemic rabbits, and furthermore examined the effects of anti-oxidant probucol on neointimal growth and the inflammatory response.

Section snippets

Balloon injury and stenting protocol

In this study, 24 male Japanese White rabbits (weight 3.1–3.3 kg) were used in research protocols that were approved by the Animal Care Committee of the University of Miyazaki (No. 2003-011). All animals received humane care according to the Guide for the Care and Use of Laboratory Animals, prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH Publication No. 86-23, revised 1996).

The rabbits were randomly separated into Group C (n=12),

Serum concentrations of TC, LDL-C, TG, and lipid peroxide

Table 1 shows the serum concentrations of TC, LDL-C, TG, and TBARS. These levels, except for TBARS of Group P, increased with time at 2, 4, and 8 weeks in both groups. Values of TC, LDL-C, and TG were lower in Group P than in Group C, but were not statistically significant. The TBARS level was significantly lower in Group P than in Group C. The weights of both groups of rabbits increased similarly (data not shown).

Luminal stenosis after balloon injury and stent implantation

Angiographs of rabbit iliac arteries obtained 8 weeks after balloon injury (right

Discussion

The present study demonstrates that the inflammatory response during neointimal development differs after balloon injury and stent implantation. In addition, although the anti-oxidant prevented the development of stenosis after both types of vascular injury in the hyperlipidemic rabbits, it was more effective after stenting.

Restenosis is the process of luminal narrowing in an atherosclerotic artery after intervention, such as balloon angioplasty and stenting. Increasing evidence indicates that

Acknowledgements

This study was supported in part by Grants-in-Aid for Scientific Research (c) (No. 15590305, 16590284) and for the 21st COE Research (Life Science) from the Ministry of Education, Science, Sports, and Culture, Japan.

References (45)

  • C. Mold et al.

    Regulation of complement activation by C-reactive protein

    Immunopharmacology

    (1999)
  • M. Nakatani et al.

    Mechanisms of restenosis after coronary intervention: difference between plain old balloon angioplasty and stenting

    Cardiovasc. Pathol.

    (2003)
  • R. Oshima et al.

    Probucol treatment attenuates the aortic atherosclerosis in Watanabe heritable hyperlipidemic rabbits

    Atherosclerosis

    (1998)
  • H. Sun et al.

    C-reactive protein in atherosclerotic lesions: its origin and pathophysiological significance

    Am. J. Pathol.

    (2005)
  • K. Watanabe et al.

    Preventive effects of probucol on restenosis after percutaneous transluminal coronary angioplasty

    Am. Heart J.

    (1996)
  • K. Yasojima et al.

    Generation of C-reactive protein and complement components in atherosclerotic plaques

    Am. J. Pathol.

    (2001)
  • H. Yokoi et al.

    Effectiveness of an antioxidant in preventing restenosis after percutaneous transluminal coronary angioplasty: the Probucol Angioplasty Restenosis Trial

    J. Am. Coll. Cardiol.

    (1997)
  • L.C.P. Azevedo et al.

    Oxidative stress as a signaling mechanism of the vascular response to injury: the redox hypothesis of restenosis

    Cardiovasc. Res.

    (2000)
  • J.A. Berliner et al.

    Minimally modified low density lipoprotein stimulates monocyte endothelial interactions

    J. Clin. Invest.

    (1990)
  • G. Cote et al.

    Effects of probucol on vascular remodeling after coronary angioplasty. Multivitamins and Probucol Study Group

    Circulation

    (1999)
  • A. Farb et al.

    Pathology of acute and chronic coronary stenting in humans

    Circulation

    (1999)
  • A. Farb et al.

    Morphological predictors of restenosis after coronary stenting in humans

    Circulation

    (2002)
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