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CARDIOVASCULAR
Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina (F.G.S., G.P.E., J.W.H., L.L.C., S.S.C., J.P.M, C.G.S., R.E.S., J.S.I.) and the Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina (F.G.S., J.S.I.)
Received March 15, 2006; accepted June 2, 2006.
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Abstract |
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; Thompson and Squire, 2002; Schellings et al., 2004; Wainwright, 2004). Specifically, the induction and activation of a family of matrix proteases, termed the matrix metalloproteinases (MMPs), have been demonstrated to occur in patients and animal models of myocardial injury and remodeling (Creemers et al., 2001; Bradham et al., 2002; Kaden et al., 2003; Mukherjee et al., 2003; Yarbrough et al., 2003; Nian et al., 2004; Tziakas et al., 2004; Wainwright, 2004). The MMPs are a large family of proteolytic enzymes and can degrade a number of matrix proteins, process biologically active signaling molecules and growth factors, and degrade a number of transmembrane proteins (Woessner, 1998; McDonnell et al., 1999; McCawley and Matrisian, 2001; Steffensen et al., 2001; Brinckerhoff and Matrisian, 2002; Coussens et al., 2002; Overall et al., 2004; Tsuruda et al., 2004). Using murine transgenic constructs, genetic deletion of a specific MMP type can favorably modify the post-MI remodeling process, whereas deletion of endogenous inhibitors of MMPs (TIMPs) can accelerate adverse LV remodeling (Creemers et al., 2000; Ducharme et al., 2000; Ikonomidis et al., 2005; Matsumura et al., 2005). In other studies, it has been demonstrated that pharmacological strategies that provide for inhibition of active MMPs within the myocardium can significantly attenuate the post-MI remodeling process (Creemers et al., 2001; Mukherjee et al., 2003; Yarbrough et al., 2003; Ikonomidis et al., 2005). Thus, a cause-effect relationship between induction of MMP activity and LV remodeling post-MI has emerged. Whereas the MMP gene gain/loss of function studies will provide important mechanistic insight into the regulation and activity of myocardial MMPs in the remodeling process, it is likely that a pharmacological MMP inhibition will be the approach to be considered in clinical application. However, several outstanding issues regarding the utility of pharmacological MMP inhibition exist. First, initial clinical studies demonstrated adverse systemic side effects with prolonged MMP inhibition (Bloomston et al., 2002; Coussens et al., 2002; Overall and Lopez-Otin, 2002; Vihinen and Kahari, 2002). Therefore, the duration of treatment with MMP inhibition after MI must be considered. Second, the effects of long-term MMP inhibition on LV myocardial structure and function post-MI have not been examined. Finally, although past studies have demonstrated a favorable effect of MMP inhibition on LV structure and function in animal models of MI, they have been of short duration (Creemers et al., 2000, 2001; Mukherjee et al., 2003; Yarbrough et al., 2003; Ikonomidis et al., 2005). Thus, the direct effects of MMP inhibition on survival after MI induction remain to be established. The present study was designed to address these issues by surgically inducing an MI in a large sample of mice and performing a long-term survival study (6 months) after treatment with a continuous MMP inhibition post-MI. LV structure and function were examined in the surviving mice to assess the effects of prolonged MMP inhibition in this murine post-MI model. |
Materials and Methods |
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Experimental Design. At 3 days post-MI, 131 mice were assigned to undergo MMP inhibition using a broad-spectrum MMP inhibitor [MI-MMPi: PD200126, 7.5 mg/day/p.o. (formerly PD166793; Parke-Davis, Detroit, MI); Pfizer, Groton, CT] or to remain untreated. Oral administration of this MMP inhibitor in animal models of LV remodeling have been described and characterized previously (Spinale et al., 1999; Peterson et al., 2001; Mukherjee et al., 2003; Ikonomidis et al., 2005). The mice were coded by ear tag and assigned in an alternating fashion to the MMP inhibitor or untreated groups. The treatment assignments and codes were not broken until the completion of the study. The dose of MMP inhibitor used in this study achieved a steady-state plasma level of 8.5 ± 2.2 mg/ml, which has been demonstrated previously in ex vivo studies to achieve a significant broad-spectrum MMP inhibitory effect and has been used in rodents to achieve MMP inhibition (Peterson et al., 2001; Ikonomidis et al., 2005). Whereas this compound effectively inhibits MMP activity, it does not affect other metalloproteases, such as angiotensin-converting enzyme, neutral endopeptidases, or tumor necrosis factor-
-converting enzyme (Spinale et al., 1999; Peterson et al., 2001; Mukherjee et al., 2003). With respect to MMP inhibitory specificity, the inhibitory potency of PD166793 for the MMP catalytic domain (effective inhibitory concentration; EC50) ranges from 7.9 µM for MMP-9 to 0.008 µM for MMP-13 (Spinale et al., 1999; Peterson et al., 2001). The plasma levels achieved in the present study significantly exceeded the EC50 for all of the major MMP types by approximately 10-fold. In a past study, it has been demonstrated that this MMP inhibitor has a high myocardial penetrance and significantly inhibited myocardial MMP activity (Spinale et al, 1999; Mukherjee et al., 2003). The rationale for initiating MMP inhibition at 3 days post-MI was 2-fold. First, this allowed for screening and confirmation of an MI in this murine model before treatment assignment. Second, the intent of this study was to examine post-MI remodeling and not to interfere with the acute phase of the myocardial wound healing process. The mice were examined in the morning and afternoon of each day. The duration of this study was 6 months.
LV Function, Histomorphometric, and Biochemical Measurements at 6 Months. Terminal studies were performed in all of the surviving mice at 6 months. A cohort of age-matched male mice (n = 16) was included in these studies to serve as reference controls. LV function was first assessed by anesthetizing the mice as described in the previous section, and two-dimensional echocardiography was performed to obtain LV end-diastolic volumes (in microliters) and ejection fraction (%) using conventional methods (Collins et al., 2003). After the echocardiographic study and under 5% isoflurane, a sternotomy was performed, and 0.5 ml of 0.1 mM cadmium chloride was injected into the LV to achieve mechanical arrest in diastole. The heart was quickly removed and placed in iced saline, and the LV was trimmed away and weighed. The LV was then divided into two equivalent sections along the long axis with the transected MI region. One LV section was then fixed in a 4% formalin solution overnight, embedded in paraffin, and used for histomorphometrics. The second LV section was rapidly frozen in a dry-ice slurry and maintained at –70°C until use for biochemical analysis.
For the histomorphometry studies, sections (5 µm) were stained with hematoxylin and eosin for measurement of MI size and myocyte cross-sectional area using computer-assisted methods described previously (Spinale et al., 1999; Creemers et al., 2000; Ikonomidis et al., 2005). In brief, MI size was based on performing computer-based planimetry (Sigma Scan; Media Cybernetics, Silver Spring, MD) on the entire endocardial and epicardial borders of the LV section and demarcating the MI region. The MI size was expressed as a percentage of the total LV area (Ikonomidis et al., 2005). For myocyte cross-sectional area, the myocyte profiles were digitized using a final magnification of 60x, and a minimum of 100 profiles were measured from each LV section (Spinale, 1999). Additional LV sections were stained with picrosirius red for fibrillar collagen, and the percentage area of collagen within the remote and MI regions of the LV was computed (Spinale et al., 1999; Mukherjee et al., 2003; Yarbrough et al., 2003; Ikonomidis et al., 2005).
To examine whether relative changes in MMP or TIMP profiles occurred in the treated and untreated MI groups at 6 months, substrate zymography was performed to assess the relative content of the gelatinases MMP-2 and MMP-9 (Heymans et al., 1999; Peterson et al., 2001; Chapman et al., 2003). Immunoblotting was performed for MMP-13 as well as for TIMP-1 and -4 using methods described previously (Peterson et al., 2001; Mukherjee et al., 2003; Yarbrough et al., 2003; Ikonomidis et al., 2005). The previously frozen fullthickness LV myocardial sections were homogenized using ice-cold MMP extraction buffer (10 mM cacodylic acid, 150 mM NaCl, 0.01 mM ZnCl2, 20 mM CaCl2, 2 mM NaN3, and 0.1% Triton X-100, pH 5.0). For zymography, the myocardial homogenates (10 µg of total protein) were subjected to electrophoretic separation containing a denatured collagen substrate (1 mg/ml type III gelatin; Sigma, St. Louis, MO). For immunoblotting, myocardial extracts (10 µg) were loaded onto 4 to 12% BisTris gels and subjected to electrophoretic separation. The separated proteins were then transferred to a nitrocellulose membrane. After a blocking and washing step, the membranes were incubated for 1 h in antisera (1:5000 dilution) corresponding to MMP-13 (AB8114; Chemicon, Temecula, CA): TIMP-1 (RP2T1; Triple Point Biologics, Forest Grove, OR) or TIMP-4 (AB816; Chemicon). The membranes were then washed and incubated with a secondary antibody (1:5000; Vector Laboratories, Burlingame, CA) conjugated with horseradish peroxidase. Signals were detected by chemiluminescence (Western Lightning; PerkinElmer, Inc., Boston, MA). The zymograms and immunoblots were digitized and analyzed (Gel Pro Analyzer; Media Cybernetics). Recombinant standards (Chemicon) were included in all zymograms and immunoblots as positive controls and to standardize the digital analysis.
Data Analysis. For the survival portion of the study, survival curves were constructed using Kaplan-Meier probability estimates. The median survival time, i.e., the time at which 50% of the sample group died, was compared between the two groups using a ChiSquare analysis. In addition, comparisons of survival were compared using a stratified log rank test. LV function and geometry were compared between the two groups using a t test. For the morphometric data, the measurements of cross-sectional area and collagen area were first confirmed to conform to a Gaussian distribution, subjected to analysis of variance, and finally to Tukey's test for mean separation. For the zymography and immunoblotting studies, all measurements were performed in duplicate, and the zymographic/immunoreactive signals were analyzed using densitometric methods (Gel Pro Analyzer; Media Cybernetics) to obtain two-dimensional integrated optical density values. The integrated optical density values were then computed as a percentage of non-MI control values where the control values were set to 100%, and comparisons were performed by a separate t test. Results are presented as mean ± S.E.M. Values of p < 0.05 were considered statistically significant. All statistical procedures were performed using the STATA statistical software package (Statacorp, College Station, TX).
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Results |
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LV function and geometry by echocardiography were assessed in the mice surviving 6 months in the MI-only group (n = 27) and the MI-MMPi group (n = 17) and were compared with an age-matched reference control group (n = 16). Representative LV echocardiograms are shown in Fig. 2. LV end-diastolic volume increased in the MI-only and MI-MMPi groups (154 ± 14 and 219 ± 24 µl) compared with control (67 ± 4 µl, p < 0.05), with a greater degree of dilation in the MI-MMPi group (p < 0.05). LV ejection fraction was reduced to the same degree in the MI-MMPi and MI-only groups (30 ± 3 versus 30 ± 3%) compared with control (61 ± 1%, p < 0.05).
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Representative MMP/TIMP zymograms and immunoblots are shown in Fig. 5. Relative MMP-2 (72-kDa band) and MMP-9 (92-kDa band) levels were determined from zymography, and MMP-13, TIMP-1, and TIMP-4 levels were determined from immunoblotting. Myocardial MMP-2 levels appeared increased in the MI-only group from reference controls but did not reach statistical significance (131 ± 16%, p = 0.30). MMP-2 levels increased from control and MI-only values in the MI-MMPi group (198 ± 17%, p < 0.05). Relative MMP-9 levels increased in a similar direction in the MI-only and MI-MMPi group compared with reference controls (684 ± 139 and 639 ± 115%, respectively, p < 0.05). In contrast, MMP-13 levels concordantly decreased in both the MI and MI-MMPi groups from reference control values (65 ± 17 and 61 ± 11%, p < 0.05). TIMP-1 levels were similar to reference controls in the MI and MI-MMPi groups (123 ± 32 and 148 ± 50%, p > 0.40). TIMP-4 levels were unchanged from reference control values in the MI-only and MI-MMPi groups (94 ± 18 and 96 ± 22%, p > 0.70).
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Discussion |
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3 months), a worsening survival was observed. Second, chronic MMP inhibition resulted in a greater degree of LV dilation, hypertrophy of surviving myocytes, and increased collagen content within the remote myocardium. Taken together, these results, as well as results from past reports (Heymans et al., 1999; Ducharme et al., 2000; Creemers et al., 2001; Mukherjee et al., 2003; Yarbrough et al., 2003; Ikonomidis et al., 2005; Matsumura et al., 2005), would suggest that MMP inhibition early post-MI can provide beneficial effects on LV remodeling and survival, but prolonged broad-spectrum MMP inhibition is associated with adverse effects on LV remodeling and survival. Thus, a specific temporal window for therapeutic intervention probably exists with respect to regulating MMP activity in the post-MI period.
A number of past studies have examined the effects of MMP inhibition in animal models of post-MI remodeling (Creemers et al., 2001; Mukherjee et al., 2003; Yarbrough et al., 2003; Ikonomidis et al., 2005; Matsumura et al., 2005). These studies have been focused upon the early post-MI period (up to several weeks post-MI) and have uniformly documented a reduction in the degree of LV dilation. Moreover, these past studies have demonstrated that the relative reduction in the adverse remodeling process that was achieved by MMP inhibition was not due to differences in the degree of initial injury (i.e., infarct size) but rather due to modifying the proteolytic processes that occurred after MI. The present study was designed to address several potential confounding factors that would independently have influenced remodeling and survival in the post-MI period. First, mice underwent MMP inhibition following confirmation of an equivalent wall motion abnormality post-MI. Our past studies have documented that a relatively uniform early MI size is achieved through the surgical procedure employed in the present study (Creemers et al., 2003; Ikonomidis et al., 2005). MI sizes were identical in the surviving mice assigned to the two groups; thus, it is unlikely that differences in MI size significantly influenced the findings with respect to survival and LV remodeling. Second, only male mice were used in the present study, because gender can influence LV function and remodeling in the post-MI period in mice (Cavasin et al., 2004). Third, MMP inhibition was instituted at 3 days post-MI. This time point was chosen to avoid interference with the initial wound healing response that may have occurred with early MMP inhibition (Creemers et al., 2000; Steffensen et al., 2001; Frangogiannis et al., 2002; Thompson and Squire, 2002; Nian et al., 2004).
The present study is the first to demonstrate that a time-dependent effect on modifying myocardial MMP activity exists within the post-MI period with respect to survival and LV remodeling. However, there have been a number of past studies that have examined the short-term effects of modifying MMP induction/activity in the early post-MI period (Creemers et al., 2000, 2001, 2003; Ducharme et al., 2000; Mukherjee et al., 2003; Yarbrough et al., 2003; Ikonomidis et al., 2005; Matsumura et al., 2005). For example, deletion of either the MMP-9 or MMP-2 gene in mice reduced the relative incidence of myocardial rupture and LV dilation in the first 2 weeks after MI (Heymans et al., 1999; Ducharme et al., 2000; Matsumura et al., 2005). We have reported previously that TIMP-1 gene deletion, which would reduce the relative degree of endogenous MMP inhibition, was associated with an acceleration of adverse LV remodeling within the first 14 days post-MI (Creemers et al., 2003; Ikonomidis et al., 2005). Using the same MMP inhibitor employed in the present study, this laboratory has demonstrated previously that broad-spectrum MMP inhibition significantly attenuated the degree of infarct expansion in a porcine model of MI in which the greatest effect was observed within the first 30-day period (Mukherjee et al., 2003). These past results, along with the findings of the present study, would suggest that MMP activation holds the greatest biological significance within the first 30 days post-MI, with respect to favorably affecting LV structure, function, and survival.
A clear cause-effect relationship has been established between the early LV dilation, which occurs after MI, and MMP activation (Heymans et al., 1999; Rohde et al., 1999; Creemers et al., 2001; Mukherjee et al., 2003; Yarbrough et al., 2003; Ikonomidis et al., 2005; Matsumura et al., 2005). Whereas these initial results provided the rationale for aggressively pursuing the MMP system as a therapeutic target in the post-MI period, the results from the present study provide the first results to suggest that this approach may not necessarily be associated with favorable effects on the LV remodeling process when MMP activity is modified for an extensive period of time post-MI. In the surviving mice that had undergone 6 months of MMP treatment, the relative degree of LV dilation was greater than time-matched untreated post-MI mice. This finding was unexpected since short-term MMP inhibition studies have uniformly demonstrated a significant attenuation in LV volumes post-MI (Spinale et al., 1999; Bloomston et al., 2002; Mukherjee et al., 2003; Yarbrough et al., 2003; Ikonomidis et al., 2005). Whereas the mechanisms for this effect remain unclear, it must be recognized that the myocardial remodeling is a multifactorial process and that targeting a single proteolytic pathway will probably be insufficient to completely abrogate post-MI remodeling (Frangogiannis et al., 2002; Thompson and Squire, 2002; Nian et al., 2004; Schellings et al., 2004; Wainwright, 2004). Additional evidence that prolonged MMP inhibition differentially and adversely affected the LV remodeling process post-MI proved that myocyte cross-sectional area was reduced and relative collagen content within the viable myocardial regions was increased. The LV chamber dilation coupled with the reduction in myocyte cross-sectional area would suggest that increased myocyte length occurred with prolonged MMP inhibition. In short-term post-MI studies, MMP inhibition was not associated with increased myocardial collagen accumulation (Peterson et al., 2001; Mukherjee et al., 2003; Ikonomidis et al., 2005). Taken together, these observations imply that prolonged MMP inhibition post-MI failed to maintain the favorable effects on LV remodeling that can be achieved with short-term MMP inhibition.
The present study used a broad-spectrum MMP inhibitor, defined as one that inhibits all major classes of MMPs (Woessner, 1998; McDonnell et al., 1999; Brinckerhoff and Matrisian, 2002; Coussens et al., 2002). This MMP inhibitor has been characterized previously in rodent and large animal models of LV remodeling and dysfunction (Peterson et al., 2001; Mukherjee et al., 2003). However, it is unlikely that broad-spectrum MMP inhibition will be used clinically because of systemic effects associated with prolonged use (Spinale et al., 1999; Peterson et al., 2001). It is now recognized that a differential profile of MMPs exists in the post-MI period (Bloomston et al., 2002; Overall and Lopez-Otin, 2002; Vihinen and Kahari, 2002). Thus, pharmacological strategies that selectively target those MMP types, which are induced post-MI and are likely contributory toward adverse LV remodeling, would hold biological and clinical significance. Indeed, more selective MMP inhibitors have been employed in post-MI animal models and have attenuated the degree of adverse LV remodeling (Yarbrough et al., 2003). Thus, whether and to what degree more selective MMP inhibitors would exert the same effects as those observed in the present study warrant investigation. Additional experimental design considerations/limitations of the present study also deserve comment. Sham control (non-MI) mice with and without prolonged MMP inhibition were not included as a study cohort. Thus, whether and to what degree surgical manipulation or drug treatment alone, in the absence of an MI, may have influenced long-term survival or LV remodeling could not be addressed. In our initial dose-determination studies, preliminary results revealed no adverse effects (systemic or cardiac) of MMP inhibition in non-MI mice with up to 6 months of treatment. However, it cannot be ruled out that prolonged MMP inhibition caused systemic toxicity that may have contributed to the differences in long-term survival.
In the present study, relative levels of the predominant interstitial collagenase MMP-13 were reduced in both the untreated and MMP inhibition groups at 6 months post-MI, whereas MMP-9 levels were increased. The relative reduction in MMP-13 at late post-MI time points would favor collagen accumulation, particularly in the MI region. In the MMP inhibition group, the reduction in MMP-13, coupled by local inhibition of MMP activity in general, would be one mechanism for the increased collagen accumulation in the remote region, which was observed in the present study. Although expressed by a large number of cell types, MMP-9 is abundantly expressed in inflammatory cells (McDonnell et al., 1999; Thompson and Squire, 2002; Wainwright, 2004; Woessner, 1998). Thus, the persistent increase in MMP-9 is probably reflective of localized inflammation and wound healing. What was noted in the present study was that chronic MMP inhibition was associated with a relative increase in MMP-2 levels compared with untreated MI values. In human myocardial fibroblast systems, we have demonstrated previously that prolonged exposure to the MMP inhibitor used in the present study could induce a relative increase in MMP-2 abundance (Chapman et al., 2003). However, the present study did not analyze relative mRNA MMP levels; therefore, whether and to what degree prolonged term MMP inhibition affected MMP levels at the transcriptional level remain to be established. Although further studies are warranted, the present findings suggest that prolonged broad-spectrum MMP inhibition may interfere with a feedback mechanism that regulates MMP-2 expression and/or synthesis. Nevertheless, the relative increase in MMP-2 myocardial levels, which occurred in the MMP inhibitor group, would not result in "pharmacological escape," because previously performed pharmacokinetic studies demonstrated that the dose used in the present study would still provide significant inhibition of MMP-2 (Spinale et al., 1999; Peterson et al., 2001). Results also demonstrated that relative TIMP levels were unaffected by prolonged MMP inhibition. Thus, the effects of pharmacological MMP inhibition seem to be MMP type-specific.
Several clinical studies have demonstrated a distinct temporal profile of plasma levels of MMPs and TIMPs in patients post-MI (Bradham et al., 2002; Kaden et al., 2003; Tziakas et al., 2004). Basic studies have demonstrate that the myocardial induction of MMPs is both time- and type-specific in the post-MI period (Bradham et al., 2002; Mukherjee et al., 2003; Wilson et al., 2003; Yarbrough et al., 2003). Further, recent animal studies have demonstrated the possibility of visualizing MMP activity within the intact cardiovascular system (Schafers et al., 2004; Chen et al., 2005). The present study provides the first results to suggest that a specific temporal window exists with respect to achieving a beneficial effect of broad-spectrum MMP inhibition on survival. Thus, it may be possible to integrate surrogate markers of MMP induction as well as direct imaging methods of MMP activity to identify maximal myocardial MMP activity in the post-MI period and thereby deploy pharmacological inhibition in a manner to achieve the greatest potential benefit, with respect to the prevention of adverse LV remodeling and increased survival. Although this issue remains speculative and requires further investigation, what is clear from the present study is that long-term treatment with broad-spectrum MMP inhibition in the post-MI period may have deleterious effects on LV remodeling and survival.
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: MI, myocardial infarction; LV, left ventricle; MMP, matrix metalloproteinase; MMPi, MMP pharmacological inhibition; TIMP, tissue inhibitor of matrix metalloproteinase; PD200126 (formerly PD166793), (s)-2-(4-bromo-biphenyl-4-sulfonylamino)-3-methyl-butyric acid.
Address correspondence to: Dr. Francis G. Spinale, Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC. E-mail: wilburnm{at}musc.edu
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