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
V. Falka,b*,
P.M. Soccala,
J. Grünenfeldera,
G. Hoyta,
T. Waltherb,
R.C. Robbinsa
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
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Abstract
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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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1. Introduction
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Matrix metalloproteinases (MMPs) and tissue inhibitors to metalloproteinases (TIMPs) regulate the turnover of the cardiac extracellular matrix and modulate capillary permeability [1–3]. Upregulation of MMPs have been demonstrated after myocardial infarction, with myocardial hypertrophy and in heart failure [4–7]. The degradation of basement membranes and extracellular matrix by upregulated MMPs are, in part, responsible for the loss of vascular integrity and may play an important role in reperfusion injury following ischemia. In a rat model of lower extremity ischemia by femoral artery ligation, it was shown that acute moderate ischemia was followed by a significant transient increase in MMP-2 and -9 chiefly at the periphery of myofibres. Type IV collagen and laminin staining showed that the increase in gelatinase expression correlated with disruption of basement membranes [8]. Similar findings have been reported for induced cerebral ischemia. Along with an upregulation of MMP-2 and -9 disruption of the basal membranes with breakdown of the blood–brain barrier was found [9–11]. In various models of cardiac ischemia by coronary ligation increased MMP-2 and -9 levels have been documented [12–15] and disruption of the basal lamina has been shown to be associated with enhanced scar tissue formation in rat myocardium after ischemic injury [16].
The role of MMP activation in the acute reperfusion injury related to heart transplantation is currently not known. In a rodent model of heterotopic heart transplantation the activation of MMPs and the integrity of basal lamina in reperfused allografts and isografts was examined. The potential role of a MMP-inhibitor (Batimastat) to prevent the proteolytic activity of MMPs was evaluated.
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2. Methods
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2.1. Animal model
Adult male rats (8–10 weeks old, 230–270 g) were used. Donor (PVG, black hooded inbred strain) and recipient (ACI, August Copenhagen Irish inbred strain) were anesthetized with methoxyflurane (inhalational) and sodium pentobarbital (50 mg/kg i.p.). The donor aorta and pulmonary artery were anastomosed end-to-side to the recipient abdominal aorta and vena cava, respectively. Animals were allowed free access to food and water. The following groups (n=6) were used: C=control group – normal PVG hearts; I=isograft group – PVG hearts implanted in PVG recipients after 4 h of ischemia and explanted after 72 h of reperfusion; A=allograft group with no treatment – PVG hearts were transplanted into ACI recipients after 4 h of ischemia and explanted after 72 h of reperfusion; AT=allograft group (same protocol as group A) but additional treatment with the MMP-inhibitor Batimastat. No immunosuppressive therapy was given.
2.2. MMP-inhibition
Batimastat (British Biotech Pharmaceuticals, Oxford, UK) is a collagen-mimicking hydroxamic acid derivate that possesses potent activity against most of the major matrix metalloproteinases by reversible competition with the MMP substrate. The inhibitory concentrations (IC50) for Batimastat are 4 nM for MMP-2 and 3 nM for MMP-9, respectively. The drug is moderately active in inhibiting tumor necrosis factor-alpha conversion (TNF-alpha converting enzyme is a metalloproteinase) but does not inhibit the metalloproteinase angiotensin converting enzyme. Batimastat has an extremely poor aqueous solubility (0.003 mg/ml) and therefore requires intraperitoneal administration of a suspension (3 mg/ml of Batimastat in phosphate-buffered saline, pH 7.2, containing 0.01% Tween-80; sonication at 100 Hz for 5 min). Donors were treated with 30 mg/kg intraperitoneal injection of the MMP-inhibitor Batimastat 24 h prior to surgery. This dose gives blood concentrations in mice ranging from 100 ng/ml after 3 h to 30 ng/ml after 24 h. Recipients were treated with Batimastat at a dose of 15 mg/kg every 24 h until termination of the experiment.
2.3. Analysis of reperfusion injury
The myeloperoxidase (MPO) activity assay was based on the method described by Mullane and coworkers [17]. In brief, the tissue was disrupted by homogenizing in 10% (w/v) hexadecyltrimethyl-ammonium bromide in 50 mmol/l potassium phosphate buffer (pH 7.0) with a Polytron homogenizer (Fisher Scientific, Tustin, CA). The homogenate was sonicated on ice for 15 s, underwent three freeze-thaw cycles, and was then centrifuged at 12 000xg for 15 min. Aliquots (20 µl) of supernatant were added to the assay buffer (30 µl of 40 mmol/l O-dianisidine hydrochloride, 12 µl of 25 mmol/l H2O2, and 1.938 ml of 50 mmol/l potassium phosphate buffer, pH 7.0). Absorbance at 470 nm was measured by spectrophotometry (Beckman Instruments, Fullerton, CA). One unit of Myeloperoxidase is defined as the activity degrading 1 µmol of peroxide/minute at 25°C. TNF-alpha was measured using a solid-phase sandwich ELISA kit (BioSource, International, Camarillo, CA) to determine TNF-concentrations in myocardium homogenates [18]. This immunoassay recognizes both natural and recombinant rat TNF-alpha. A specific anti-TNF-antibody was coated onto the wells of the microtiter strips. Standards of known TNF-contents, control specimens, and unknown samples were pipetted into the wells followed by the addition of biotinylated second antibody. After a first incubation and the removal of excess second antibody, streptavidin peroxidase was added which bind to the biotinylated antibody to complete the four-member sandwich. After a second incubation and washing to remove all the unbound enzyme, a substrate (tetramethyl benzidine) solution was then added to produce color. The intensity of this colored product is directly proportional to the concentration of TNF-present in the sample. Absorbance was read with a microtiter plate reader at 450 nm.
2.4. Immunostaining for basal membrane Laminin and Collagen IV
Samples were fixed in formalin. Hematoxylin-Eosin staining was performed for assessment of rejection and ischemic damage. Sections of 4 µm were cut and incubated at room temperature with primary antibodies to Laminin (AHP 420 Serotec) and Collagen IV (COL-94 BioGenex Laboratories Inc, San Ramon, CA). Biotinylated antibodies (MultiLink QP900-9L, Biogenex) were used as secondary antibodies. Diaminobenzamine was used for staining of secondary antibodies and Hematoxylin was used for counterstaining.
2.5. Heart tissue MMP extraction
Snap frozen (-80°C) heart tissue was weighed and homogenized in lysis buffer. After protein content measurement by Bicinchoninine acid assay, supernatant was incubated with gelatin-sepharose for 1h. After brief centrifugation (500xg) and washing, the pellet was resuspended in an elution buffer and incubated for 30 min. After centrifugation for 5 min (500xg) the supernatants were then loaded to electrophoretic gels (sodium dodecyl sulfate-page).
2.6. Gelatin-zymography
Two ml of non-reducing sample buffer were added to eight ml of sample, and loaded onto 10% zymogram gelatin minigels (Novex, San Diego, CA). Gels were run at 35 mA for 2.5 h. After migration, gels were incubated in 2.5% Triton-X 100 for 2x1 h at room temperature, washed and further incubated for 16 h in TNCA, at 37°C. Gels were stained for 90 min in Coomassie blue and destained in 30% methanol/10% acetic acid, four times for 5, 15, 30 and 60 min, respectively. White bands on a blue background indicated zones of digestion corresponding to the presence of different MMPs identified on the basis of their molecular weight. The pro- and activated forms of gelatinase B and A were identified at 92 kDa (proMMP-9) 82 kDa (MMP-9), 72 kDa (proMMP-2) and 62 kDa (MMP-2), respectively. Serial dilutions of proMMP-9 and -2 standards (10 µg/100 µl; Calbiochem-Novabiochem, San Diego, CA) were used to draw a standard curve. After screening, zymography was repeated for all the samples at several dilutions in order to quantify the samples in the linear range of detection (Fig. 1)
. Bands were scanned using a densitometer (GS-700 Bio-Rad, CA, USA), quantification was performed using the Multianalyst software (Bio-Rad), and results were expressed in µg/ml.
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Fig. 1. Gelatin zymography of ventricular extracts. S=standard; C=control hearts; A=allografts; AT=allografts with Batimastat treatment; and I=isografts.
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2.7. MMP gelatinase activity assay
After MMP extraction, samples were standardized according to their assessed protein content and submitted without pre-activation step to the MMP gelatinase activity assay kit (ECM kit 700, Chemicon Inc, Temecula-CA,USA) according to manufacturer instructions.
2.8. Statistics
Data are presented as mean±standard deviation. For comparison of means one-way analysis of variance (ANOVA) was performed using Scheffe's test for post-hoc analysis. A P<0.05 was considered statistically significant.
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3. Results
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There was a significant increase of MMP-2 expression in the untreated allografts (2271±571 µg/ml) as compared to controls (683±139 µg/ml) and the treated allografts (259±140 µg/ml, P<0.05, Fig. 2)
. Although the pro-MMP-2 expression was equally high in the iso- and untreated allograft group (75±23 versus 62±30 µg/ml, Fig. 3)
, 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 untreated allografts and isografts as opposed to control hearts and MMP-inhibited allografts. MMP-9 was completely inhibited by Batimastat (Fig. 3). Collagenolytic activity was lower in treated as compared to untreated allografts (538±140 versus 384±97 µg/ml, P<0.05, Fig. 4)
, demonstrating effective inactivation of MMPs with Batimastat administration. This was also reflected in in-situ zymograms. In the treated allograft group a lesser extent of basal lamina alterations could be demonstrated by laminin and collagen IV staining, respectively. Fig. 5a
shows a representative example of the untreated allograft with only little staining for laminin demonstrating digestion of the basal lamina. In treated allograft (Fig. 5b) the basal laminar surrounding the myocytes is clearly visible.
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Fig. 2. Results for MMP-2. S=standard; C=control hearts; A=allografts; AT=allografts with Batimastat treatment; and I=isografts. Batimastat inhibits MMP-2 activity.
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Fig. 3. Results for proMMP-2, proMMP-9 and MMP-9. S=standard; C=control hearts; A=allografts; AT=allografts with Batimastat treatment; and I=isografts.
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Fig. 4. Results of collagenolytic activity. S=standard; C=control hearts; A=allografts; AT=allografts with Batimastat treatment; and I=isografts. Marked decrease of proteolytic activity with inhibition of metalloproteinases.
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Fig. 5. DAB-Staining for Laminin. In the untreated allograft group disruption of basal membranes is shown by absence of Laminin (a); whereas in the Batimastat-treated sample (b) intactness of basal membranes is demonstrated (magnification x400).
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Myeloperoxidase activity was significantly higher in untreated as compared to treated allografts (0.39±0.08 versus 0.28±0.06 pg/mg total protein; P<0.05). There was also a trend towards a reduction in TNF-alpha levels in the treated group (170±72 versus 145±123 µ/mg total protein), however this difference failed to reach statistical significance.
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4. Discussion
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Donor organs are subjected to global cold ischemia, warm ischemia and blood reperfusion. These events are believed to impair graft function and aggravate both acute and chronic rejection episodes. Reperfusion injury is an inflammatory cell-mediated response that causes tissue damage immediately following transplantation. Recent studies have shown, that activation of metalloproteinases may play an important role in cardiac reperfusion injury [12–15]. This study showed that after 4 h of ischemia and 72 h of reperfusion there is an increase in metalloproteinase expression in transplanted hearts which is associated with a massive degradation of basement membranes. Both the proform and the activated form of metalloproteinases were evaluated. While an increase of the proform was found in both allo- and isografts, only the active form of MMP-2 but not MMP-9 was increased in allografts as compared to isografts. This finding suggests additional activation of proMMP-2 by immunologic mechanisms. The MMP inhibitor Batimastat was effective in decreasing both MMP-9 as well as MMP-2 to control levels. In order to evaluate the actual proteolytic activity of the extracted samples, a type IV collagenase activity assay was performed. After 4 h of ischemia and 72 h of reperfusion the proteolytic activity was increased in both allo- and isografts, although to a lesser extent in the latter. Batimastat inhibited the proteolytic activity, demonstrating the involvement of MMP-2 and -9 in the digestion of type IV collagen. Type IV collagen and laminin are the key components of the basal lamina in the myocardium. The basal lamina forms a microskeleton, which separates the myocardial space into compartments for myocytes, vessels, and nerves. Staining of laminin and collagen IV gave identical results. Disruption of the basal lamina was uniquely seen after reperfusion injury. Batimastat attenuated this process by inhibiting collagen IV digestion. The results of this study thus demonstrate a correlation between the upregulation of metalloproteinases and the degradation of basal lamina following myocardial ischemia/reperfusion injury in a heart transplant model. This is in accordance with previous studies of skeletal muscle ischemia following femoral artery occlusion that showed degradation of the basal lamina along with MMP activation [8]. Similarly, ischemic injury of the brain is associated with an early appearance of activated MMP-2 and -9 with disruption of the blood–brain-barrier that is maintained by endothelial basal lamina and correlates with the extent of neuron injury [9–11].
Metalloproteinases are regulated by cytokines. Transgenic mice with an overexpression of TNF-alpha develop heart failure due to remodeling of the extracellular matrix that is paralleled by an increase in MMP-2 and -9 expression [19]. Rat cardiac fibroblast cultures treated with TNF-alpha similarly cause MMP activation [20]. Tumor necrosis factor-alpha converting enzyme is a membrane-bound disintegrin metalloproteinase that processes the membrane-associated cytokine pro TNF-alpha to its mature soluble form. Batimastat not only competitively inhibits MMPs but also has some inhibitory function against TNF-converting enzyme and thus may decrease TNF-alpha. Although we could not demonstrate a significant reduction of TNF-alpha in the treatment group, there was a trend towards lower TNF-alpha levels. Batimastat may therefore have a synergistic effect by lowering TNF-alpha and direct MMP inhibition.
We did not measure TIMPs in this model. It is known from numerous reports, that expression of TIMPs is downregulated early after ischemic injury [4,21]. It has to be recognized, that the regulation of MMPs and TIMPs varies with the type and timing of the tissue insult. Two weeks after experimental infarction an increase in TIMP-1 can be observed [22] and TIMP-1 and -2 are usually upregulated with the onset of scarring and fibrosis [23]. Serial studies will therefore be needed to demonstrate the exact time course of MMP and TIMP activation and to a demonstrate a lasting effect of MMP inhibition.
Extracellular matrix proteins facilitate cell adhesion in vitro and are believed to promote T-cell activation and differentiation. After heterotopic cardiac transplantation in primates, an increased expression of MMP-2 can be found in the spindle-shape cells of acutely rejected myocardial interstitium and prior to the presence of mononuclear cell infiltration [23]. The upregulation of intragraft extracellular matrix proteins may therefore represent an integral part of the host rejection response after cardiac allograft transplantation [24]. Myeloperoxidase activity is a global marker for quantification of infiltrated inflammatory cells. Interestingly, myeloperoxidase activity was decreased in the treated allografts in this study. It is difficult to interpret this finding but the inhibition of MMPs may infact attenuate the inflammatory response. This study did not address the effect of MMP inhibition on chronic rejection. There is evidence that differential regulation of MMPs and TIMPs may also play an important role in the intimal thickening of coronary arteries typical for chronic rejection [20]. In this study, MMP-inhibition by administration of Batimastat was effective in preventing the proteolytic activity of MMPs and showed a protective effect on the integrity of basal lamina. The occurrence of basal lamina remodeling and its partial prevention by an MMP inhibitor could provide new therapeutic targets other than immunosuppression in the prevention of in transplant related reperfusion injury. A number of orally available MMP inhibitors is currently undergoing phase III trials for anticancer treatment and the results of first experimental trials for the treatment of heart failure are underway [25,26]. Further experimental studies using these drugs have to show if long-term MMP inhibition may have the potential to alter the host rejection response by preserving extracellular matrix components and preventing graft atherosclerosis.
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Footnotes
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Presented at the joint 15th Annual Meeting of the European Association for Cardio-thoracic Surgery and the Annual Meeting of the European Society of Thoracic Surgeons, Lisbon, Portugal, September 16–19, 2001.
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Abstract
1. Introduction
