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Eur J Cardiothorac Surg 2002;22:53-58
© 2002 Elsevier Science NL

Regulation of matrix metalloproteinases and effect of MMP-inhibition in heart transplant related reperfusion injury

^a Department of Cardiothoracic Surgery, Falk Cardiovascular Research Building, Stanford University School of Medicine, Stanford, CA, USA
^b Department of Cardiac Surgery, Heartcenter Leipzig, Strümpellstr. 39, 04289 Leipzig, Germany

Received 13 September 2001; received in revised form 14 March 2002; accepted 25 March 2002.

* Corresponding author. Tel.: +49-341-865-1421; fax: +49-341-865-1452
e-mail: falv{at}medizin.uni-leipzig.de

Purpose: Metalloproteinases (MMPs) regulate extracellular matrix turnover and degrade basal lamina. Aim of the study was to examine the regulation of MMPs and the effect of an MMP inhibitor in transplant related ischemia/reperfusion injury. Methods: Heterotopic cardiac transplantation was performed after 4 h of ischemia in three groups of six rats: allografts (black hooded inbred strain, PVG donor/August Copenhagen Irish inbred strain recipient); allografts treated with a competitive MMP-inhibitor (Batimastat) 15 mg/kg every 24 h; isografts (PVG donor and recipient). Normal PVG hearts served as a control. Hearts were explanted after 72 h of reperfusion. Expression of MMP-2 and -9 was measured using gelantin zymography. Proteolytic activity was measured using a gelatinase activity assay. Myeloperoxidase activity and tumor necrosis factor-alpha (TNF-alpha) were measured as markers of inflammatory response. Immunostaining for collagen IV and laminin was used to study degradation of basal lamina. Results: There was a significant increase of MMP-2 expression in allografts (2271±571 µg/ml) as compared to normal (683±139 µg/ml) and the Batimastat-treated (259±140 µg/ml, P<0.05) groups. Although pro-MMP-2 expression was equally high in the untreated iso- and allograft group (75±23 versus 62±30 µg/ml) MMP-2 expression in the isograft hearts was significantly lower (359±267 µg/ml) suggesting activation of the pro-form by an immunologic mechanism. Pro-MMP-9 levels were significantly higher in the untreated iso- and allograft groups as opposed to normal hearts and MMP-inhibited hearts. MMP-9 was completely inhibited by Batimastat treatment. Collagenolytic activity was lower in the treated group as compared to untreated allografts (538±140 versus 384±97 µg/ml, P<0.05), demonstrating effective inhibition of MMPs by Batimastat. In the treated group a lesser extent of basement membrane component alterations could be demonstrated by laminin and collagen IV staining. There was a significant reduction in myeloperoxidase activity (P=0.027) as well as lower TNF-alpha levels (ns) in the in the Batimastat treated group. Conclusion: Ischemia leads to an increase in MMP expression and degradation of basal lamina. This process is enhanced in allografts as compared to isografts suggesting additional activation of MMPs by immunologic mechanisms. MMP-inhibition is effective in preventing the proteolytic activity of MMPs and may alter the host rejection response by preserving extracellular matrix components and basement membranes.

Key Words: Matrix metalloproteinases • Heart • Transplant

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