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Clarithromycin Attenuates Acute and Chronic Rejection Via Matrix Metalloproteinase Suppression in Murine Cardiac Transplantation

Masahito Ogawa, BS^_*, Jun-ichi Suzuki, MD^_*,_*, Keiichi Hishikari, BS^_*, Kiyoshi Takayama, PhD^_*, Hiroyuki Tanaka, MD, PhD and Mitsuaki Isobe, MD, PhD^_*

^_* Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan
Department of Thoracic Surgery, Tokyo Medical and Dental University, Tokyo, Japan.

Manuscript received October 17, 2007; revised manuscript received December 13, 2007, accepted January 21, 2008.

^_* Reprint requests and correspondence: Dr. Jun-ichi Suzuki, Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519 Japan. (Email: jsuzuki.cvm{at}tmd.ac.jp).

Objectives: Clarithromycin (CAM), a major macrolide antibiotic, has many biological functions, including matrix metalloproteinases (MMPs) regulation. However, little is known about the effect of CAM in heart transplantation via MMP-9. The purpose of this study was to clarify the role of MMPs regulated by CAM in the progression of rejection.

Background: The MMPs are critical in the development of inflammation and tissue remodeling. The MMP-9 level is associated with the rejection of heart transplantation.

Methods: We orally administered CAM into murine cardiac allograft recipients. Total allomismatch combination and class II mismatch combination were used for the analysis of graft survival, pathology and molecular.

Results: Clarithromycin improved acute rejection judged by graft survival and by myocardial cell infiltrating area in a total allomismatch combination. The CAM-treated allografts showed affected expression of T-cells, macrophages, and MMP-9 in immunohistochemistry. Zymography indicated that enhanced MMPs activities were observed in nontreated hearts, whereas CAM suppressed the levels. In chronic rejection, CAM suppressed the development of graft arterial disease and myocardial remodeling compared with that of nontreatment. Clarithromycin inhibited the expression of MMP-9, whereas the treatment did not alter the expression of MMP-2 and tissue inhibitor metalloproteinase-1 in macrophages and smooth muscle cells. Inhibition of MMP-9 by CAM was associated with suppression of smooth muscle cell migration and proliferation.

Conclusions: Clarithromycin is useful to suppress allograft remodeling, because it is critically involved in the prevention of cardiac rejection through the suppression of MMP-9.

Abbreviations and Acronyms   CAM = clarithromycin   GAD = graft arterial disease   DMEM = Dulbecco's modified Eagle's medium   ICAM = intercellular adhesion molecule   IL = interleukin   MHC = major histocompatibility complex   MMP = matrix metalloproteinase   mRNA = messenger ribonucleic acid   NF-B = nuclear factor-kappa B   RNA = ribonucleic acid   SMC = smooth muscle cell   TIMP = tissue inhibitor metalloproteinase