ONO-4817, a novel matrix metalloproteinase inhibitor, attenuates allograft vasculopathy in a rat cardiac transplant.
BACKGROUND
Cardiac allograft vasculopathy (CAV), a disorder characterized by rapid development and progression of obliterative vasculopathy in the transplanted heart, continues to be a major cause of graft failure in long-surviving human transplants. The mechanisms and histopathologic processes of CAV remain unknown. Previous animal studies have shown that inhibition of matrix metalloproteinase (MMP) prevents migration and proliferation of smooth muscle cells in CAV. In this study, we hypothesized that MMPs may be expressed in and may play an important role in CAV.


METHODS
An F344-to-WKAH rat heterotopic heart transplantation model was used. Tacrolimus was administered intramuscularly 14 days after transplantation to prevent acute rejection and to allow the development of CAV. We divided the animals into 2 groups according to post-operative treatment: an ONO group received an MMP inhibitor (ONO-4817) daily by oral gavage for 14 days after transplantation (n = 6), and a control (n = 6) group received no treatment. Grafts were harvested 60 days after treatment.


RESULTS
Immunohistochemical staining revealed that MMP-2 and tissue inhibitors of metalloproteinase-2 (TIMP-2) were expressed more strongly in the neointima and media of the control CAV animals than in the ONO-CAV animals. The animals given ONO-4817 exhibited a significant decrease in the percentage of affected vessels, in the percentage of intimal proliferation, in the intima-to-media ratio, and in the expression of MMP-2 and TIMP-2.


CONCLUSIONS
These results suggest that MMP-2 and TIMP-2 play an important role in the development of CAV and that the use of an MMP inhibitor (ONO-4817) may prevent neointimal proliferation in patients with CAV.
Hariya
Akifusa
A
Department of Thoracic and Cardiovascular Surgery, Juntendo University School of Medicine, Tokyo, Japan. ahariya@toranomon.gr.jp
Takazawa
Kenji
K
Yamamoto
Taira
T
Amano
Atsushi
A
D000818:Animals; D003327:Coronary Disease / Q000473:pathology / Q000517:prevention & control*; D003331:Coronary Vessels / Q000473:pathology; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000494:pharmacology; D061965:Matrix Metalloproteinase Inhibitors; D010647:Phenyl Ethers / Q000494:pharmacology*; D011183:Postoperative Complications / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains; D016559:Tacrolimus / Q000627:therapeutic use; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000494:pharmacology; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D061965:Matrix Metalloproteinase Inhibitors; C414368:N-hydroxy-5-ethoxymethyloxy-2-methyl-4-(4-phenoxybenzoyl)aminopentanamide; D010647:Phenyl Ethers; D019716:Tissue Inhibitor of Metalloproteinase-2; D020778:Matrix Metalloproteinase 2; D016559:Tacrolimus