Original Article

Journal of Nuclear Cardiology

, Volume 16, Issue 5, pp 753-762

First online:

Open Access This content is freely available online to anyone, anywhere at any time.

Dual molecular imaging for targeting metalloproteinase activity and apoptosis in atherosclerosis: molecular imaging facilitates understanding of pathogenesis

  • Nezam HaiderAffiliated withDepartment of Cardiology, Irvine School of Medicine, University of California
  • , Dagmar HartungAffiliated withDepartment of Cardiology, Irvine School of Medicine, University of California
  • , Shinichiro FujimotoAffiliated withDepartment of Cardiology, Irvine School of Medicine, University of California
  • , Artiom PetrovAffiliated withDepartment of Cardiology, Irvine School of Medicine, University of California Email author 
  • , Frank D. KolodgieAffiliated withCardiovascular Pathology Institute
  • , Renu VirmaniAffiliated withCardiovascular Pathology Institute
  • , Satoru OhshimaAffiliated withDepartment of Cardiology, Irvine School of Medicine, University of California
  • , Han LiuAffiliated withDepartment of Cardiology, Irvine School of Medicine, University of California
  • , Jun ZhouAffiliated withDepartment of Cardiology, Irvine School of Medicine, University of California
    • , Ai FujimotoAffiliated withDepartment of Cardiology, Irvine School of Medicine, University of California
    • , Atsuko TaharaAffiliated withDepartment of Cardiology, Irvine School of Medicine, University of California
    • , Leo HofstraAffiliated withDepartment of Cardiology, University Hospital Maastricht, Academic University of Maastricht
    • , Navneet NarulaAffiliated withDepartment of Pathology, Irvine School of Medicine, University of California
    • , Chris ReutelingspergerAffiliated withDepartment of Biochemistry, University Hospital Maastricht, Academic University of Maastricht
    • , Jagat NarulaAffiliated withDepartment of Cardiology, Irvine School of Medicine, University of California

Abstract

Background

Macrophage apoptosis and MMP activity contribute to vulnerability of atherosclerotic plaques to rupture. By employing molecular imaging techniques, we investigated if apoptosis and MMP release are interlinked.

Methods

Atherosclerosis was produced in rabbits receiving high-cholesterol diet (HC), who underwent dual radionuclide imaging with 99mTc-labeled matrix metalloproteinase inhibitor (MPI) and 111In-labeled annexin A5 (AA5) using micro-SPECT/CT. %ID/g MPI and AA5 uptake was measured, followed by histological characterization. Unmanipulated animals were used as disease controls. Correlation between MPI and AA5 uptake was undertaken and relationship confirmed in culture study of activated THP-1 monocytes.

Results

MPI and AA5 uptake was best visualized in HC diet animals (n = 6) and reduced significantly after fluvastatin treatment (n = 4) or diet withdrawal (n = 3). %ID/g MPI (.087 ± .018%) and AA5 (.03 ± .01%) uptake was higher in HC than control (n = 6) animals (.014 ± .004%, P < .0001; .0007 ± .0002%, P < .0001), and reduced substantially after diet or statin intervention. There was a significant correlation between MPI and AA5 uptake (r = .62, P < .0001), both correlated with pathologically verified MMP-9 activity, macrophage content, and TUNEL staining. In vitro studies demonstrated MMP-9 release in culture medium from apoptotic THP-1 monocytes.

Conclusions

The present study suggests that apoptosis and MMP are interrelated in atherosclerotic lesions and the targeting of more than one molecular candidate is feasible by molecular imaging.

Keywords

Radionuclides SPECT vulnerable atherosclerotic plaque