Effect of an Antimicrobial Agent on Atherosclerotic Plaques. Assessment of Metalloproteinase Activity by Molecular Imaging

Satoru Ohshima, Shinichiro Fujimoto, Artiom Petrov, Hironori Nakagami, Nezam Haider, Jun Zhou, Nobuhiro Tahara, Mariana Kiomy Osako, Ai Fujimoto, Jie Zhu, Toyoaki Murohara, D. Scott Edwards, Navneet Narula, Nathan D. Wong, Y. Chandrashekhar, Ryuichi Morishita, Jagat Narula

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Objectives: Technetium-99m-labeled matrix metalloproteinase inhibitor (MPI) was used for the noninvasive assessment of matrix metalloproteinase (MMP) activity in atherosclerotic plaques after minocycline (MC) intervention. Background: MMP activity in atherosclerosis contributes to plaque instability. Some antimicrobial agents may attenuate MMP activity. Methods: Atherosclerotic lesions were produced in 38 rabbits with a high cholesterol diet for 4 months; 5 groups of rabbits, in the fourth month, received fluvastatin (FS) (n = 6), low-dose MC (n = 7), high-dose MC (n = 7), a combination of low-dose MC and FS (n = 6), or no intervention (n = 12); 8 unmanipulated rabbits were used as disease controls. Micro-single-photon emission computed tomography imaging was performed in all animals after intravenous MPI administration, followed by pathologic characterization of the aorta. A cell culture study evaluated the effect of MC on MMP production by activated human monocytes. Results: MPI uptake was visualized best in untreated atherosclerotic animals (percent injected dose per gram MPI uptake, 0.11 ± 0.04%). MPI uptake was reduced in the FS (0.06 ± 0.01%; p < 0.0001), high-dose MC (0.05 ± 0.01%; p < 0.0001), and MC-FS (0.05 ± 0.005%; p < 0.0001) groups. Low-dose MC did not resolve MPI uptake significantly (0.08 ± 0.02; p = 0.167). There was no incremental benefit of the combination of MC and FS. MPI uptake showed a significant correlation with plaque MMP-2, and MMP-9 activity. MMP-9 release from tumor necrosis factor-α-activated macrophages was abrogated by incubation with MC. Conclusions: Molecular imaging of MMP activity in atherosclerotic plaque allows for the study of the efficacy of therapeutic interventions. MC administration resulted in substantial reduction in plaque MMP activity and histologically verified plaque stabilization. MC was found to be equally effective as FS.

Original languageEnglish (US)
Pages (from-to)1240-1249
Number of pages10
JournalJournal of the American College of Cardiology
Volume55
Issue number12
DOIs
StatePublished - Mar 23 2010

Keywords

  • atherosclerosis
  • molecular imaging
  • proteinases
  • tetracyclines

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