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Ann Thorac Surg 2001;71:1518-1523
© 2001 The Society of Thoracic Surgeons

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Original article: cardiovascular

Cardiopulmonary bypass induces the synthesis and release of matrix metalloproteinases

^a Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina, USA

Accepted for publication January 5, 2001.

^* Address reprint requests to Dr Spinale, Division of Cardiothoracic Surgery, Medical University of South Carolina, 114 Doughty St, Suite 625, Charleston, SC 29425

	Abstract

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Background. A number of cellular and molecular events can be induced after cardiac procedures requiring cardiopulmonary bypass (CPB). The matrix metalloproteinases (MMPs) are a recently discovered family of enzymes that degrade the extracellular matrix, but expression during and after CPB is unknown.

Methods. Systemic plasma MMP levels were measured in patients (n = 28, 63 ± 1 years) undergoing elective coronary revascularization requiring CPB at baseline, termination of CPB, and 30 minutes, 6 and 24 hours after CPB. Representative classes of MMP species known to degrade matrix and basement membrane components were selected for study. Specifically, the interstitial collagenases MMP-8 and MMP-13, and the gelatinases MMP-2 and MMP-9 were determined by internally validated enzyme-linked immunosorbent assay.

Results. The MMP-8 levels increased by fourfold at separation from CPB, and returned to within normal values within 30 minutes after CPB. The proenzyme forms of MMP-13 and MMP-9 increased by more than twofold at cross-clamp release and returned within normal limits within 6 hours after CPB. The proform of MMP-2 increased from baseline values at 6 and 24 hours postoperatively; likely indicative of de novo synthesis.

Conclusions. A specific portfolio of MMPs are released and synthesized during and after CPB. Because MMPs can degrade extracellular proteins essential for maintaining normal cellular architecture and function, enhanced MMP release and activation may contribute to alterations in tissue homeostasis in the early postoperative period.

	Introduction

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Cardiopulmonary bypass (CPB) continues to play a fundamental role in the performance of cardiac surgical procedures. However, the period after CPB can be associated with tissue edema, most pronounced peripherally and in the pulmonary interstitium [1, 2]. One contributory factor for extracellular fluid accumulation after CPB is alterations in vascular permeability. Although neurohormonal activation occurs after CPB and is associated with the release of bioactive peptides and cytokines [3, 4], the potential downstream mechanisms that may facilitate changes in tissue structure and function in the early period after CPB remain to be defined.

The matrix metalloproteinases (MMPs) are a large family of proteolytic enzymes responsible for extracellular matrix degradation. Certain species of MMPs have been identified in cardiovascular remodeling processes such as atherosclerotic plaque formation and aneurysm formation [5–8]. Acute induction of the MMP enzyme system has been demonstrated in inflammatory processes as well as after acute myocardial infarction [9, 10]. Bioactive peptides that are expressed after CPB can induce MMP release and activation [8]. Specifically, catecholamines and several cytokine species have been shown to upregulate MMP expression [11–13]. However, whether MMP release can occur after routine cardiac procedures and CPB remains to be defined. The goal of this study was to determine whether a specific portfolio MMP is released into the systemic circulation during and after CPB.

	Material and methods

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Patient selection and description
Patients (n = 28; 18 men, 10 women) with an average age of 63 ± 1 years undergoing elective coronary artery revascularization with planned use of cardioplegic arrest and CPB were entered into this study. Patients were entered into the study after obtaining informed consent. This protocol was reviewed and approved by the Institutional Review Board of the Medical University of South Carolina. Hemodynamic measurements were performed at induction of anesthesia, immediately after separation from the CPB circuit, and again at 30 minutes and 6 hours after CPB. Postoperative profiles are presented in Table 1 and hemodynamic indices are presented in Table 2.

MMP plasma assays
This study focused on two known classes of MMPs: the interstitial collagenases that include MMP-8 and MMP-13, and the gelatinases that include MMP-2 and MMP-9. Plasma samples were allowed to thaw on ice. Quantification of respective MMP species was done using an enzyme-linked immunosorbent assay kit (Amersham Pharmacia Biotech, Buckinghamshire, England). For MMP-2 (RPN 2617), the antisera used reacts against the proform of MMP-2 (pro-MMP-2) and does not react against the active form. For MMP-9 (RPN 2614), the antisera detects the proform of the enzyme (pro-MMP-9). For MMP-8 (RPN 2619), the antisera detects both proenzyme and active forms of MMP-8. For MMP-13 (RPN 2621), the antisera was developed to detect the proform of this enzyme. The coefficient of variation for these assay systems was 3% to 5%, does not cross-react with other proteases, and the sensitivity was 0.02 ng/mL.

The enzyme-linked immunosorbent assay procedure was similar for each MMP, using a two-site assay [14]. Plasma was added to precoated wells containing antibody to the MMP of interest and incubated at 20°C to 30°C for 1 hour. The enzyme-linked immunosorbent assay plate was washed and incubated in the primary MMP antisera conjugated to horseradish peroxidase (25°C, 1 hour). After several washes, tetramethylbenzidine/hydrogen peroxide was added to the mixture and the reaction allowed to proceed for 30 minutes. The enzyme-linked immunosorbent assay plate was immediately read at a wavelength of 450 nm (Labsystems Multiskan MCC/340, Helsinki, Finland). The concentration of plasma MMP species was determined using known MMP concentrations to generate a standard curve with each set of samples. MMP gradients across the myocardial circulation were calculated as the difference between proximal aorta and coronary sinus concentrations (proximal aorta – coronary sinus).

Data analysis
The resultant MMP concentrations were evaluated using analysis of variance for repeated measures, followed by a Bonferroni corrected t test where appropriate. Values are expressed as mean ± SEM. All statistics were performed using BMDP statistical software (Los Angeles, CA).

	Results

Top Abstract Introduction Material and methods Results Comment References

 
Systemic arterial plasma levels of MMP-8 increased nearly fivefold immediately after separation from CPB and then decreased toward normal values with longer postoperative periods (Fig 1). Plasma levels of proMMP-13 increased from baseline values immediately after cross-clamp release and remained elevated until 6 hours after CPB (Fig 2). Pro-MMP-9 levels increased threefold at cross-clamp release and decreased from these peak values within 6 hours after CPB (Fig 3). Pro-MMP-2 levels decreased from baseline at cross-clamp release, and then returned to baseline in the early period after CPB (Fig 4). However, by 6 hours after CPB, pro-MMP-2 levels increased from baseline and remained elevated at 24 hours after CPB. The myocardial gradient of pro-MMP-2 before CPB was negative, indicating a higher pro-MMP-2 concentration in the coronary sinus (Fig 5). The myocardial gradient immediately after CPB became positive, reflecting a reduced level of pro-MMP-2 in the coronary venous system. There was no significant difference in the MMP-9 myocardial gradient before versus immediately after CPB (–0.028 ± 4.43 versus 8.189 ± 7.11 ng/mL, p = 0.32).

View larger version (2K): [in this window] [in a new window]   Fig 1. Systemic arterial plasma levels for MMP-8 were determined by enzyme-linked immunosorbent assay, which recognized the pro-enzyme and active form for this MMP species. MMP-8 levels rapidly increased at separation from cardiopulmonary bypass (CPB) (*p < 0.0001) and returned to within normal levels by 30 minutes after cardiopulmonary bypass (Post CPB).

View larger version (2K): [in this window] [in a new window]   Fig 2. Systemic arterial plasma levels for MMP-13 determined by enzyme-linked immunosorbent assay, which recognized the pro-enzyme. Pro-MMP-13 (Pro-MMP-13) levels increased from baseline after cross-clamp release (*p < 0.002) and remained elevated after separation from cardiopulmonary bypass (CPB). Pro-MMP13 levels returned to within normal levels by 6 hours after cardiopulmonary bypass (Post CPB).

View larger version (2K): [in this window] [in a new window]   Fig 3. Systemic arterial levels for pro-MMP-9 (Pro-MMP-9) increased significantly from baseline values at cross-clamp release (*p < 0.001) and remained elevated until 30 minutes after cardiopulmonary bypass (Post CPB). Pro-MMP-9 levels tended to decrease toward normal values during the postoperative period, but there was significant variability in this response.

View larger version (2K): [in this window] [in a new window]   Fig 4. Systemic arterial levels for Pro-MMP-2 (Pro-MMP-2) decreased from baseline values at cross-clamp release (*p = 0.006). However, pro-MMP-2 levels increased from baseline at 6 hours after cardiopulmonary bypass (Post CPB) and remained elevated at 24 hours after cardiopulmonary bypass (*p < 0.05).

View larger version (2K): [in this window] [in a new window]   Fig 5. To determine whether the myocardium is an important source of MMPs, the myocardial gradient was computed. This gradient became positive after cardiopulmonary bypass (Post CPB), suggesting bypass-induced proenzyme binding or activation across the myocardium. (n = 20, **p = 0.06; Pre CPB = before cardiopulmonary bypass.)

	Comment

Top Abstract Introduction Material and methods Results Comment References

There have been approximately 20 species of MMPs identified that exhibit differential proteolytic activity against extracellular proteins [16–18]. The present study demonstrated increased release of several MMP species into the systemic vascular compartment during and after CPB. The interstitial collagenases are a group of MMPs that degrade native collagen fibrils within the extracellular space and include MMP-1, MMP-8, and MMP-13 [19]. MMP-1 is a predominant form of interstitial collagenase that has been localized to many tissue types including the myocardium [14, 19]. Interestingly, MMP-1 does not appear to be upregulated in chronic cardiac disease states [14]. In preliminary studies, MMP-1 was not detectable in plasma of patients undergoing CPB. However, it is possible that MMP-1 is present in plasma but was below detection limits of the assay system. In the present study, a robust increase in MMP-8 and MMP-13 occurred after separation from CPB. MMP-8 is also termed neutrophil collagenase, indicating that this is the primary cell type that releases this MMP [19]. MMP-8 degrades triple helical regions of the interstitial collagens as well as proteogylcans. MMP-13 is also termed collagenase-3 and has been primarily identified in pathologic processes such as neoplasms [19]. In normal tissue, the relative expression of MMP-13 is quite low and therefore, increased production of this particular collagenase has been implicated to participate in pathologic remodeling processes. For example, recent clinical studies have identified increased myocardial levels of MMP-13 in severe heart failure as well as in atheromatous plaque [10, 14]. One of the important findings from the present study was that an acute release of MMP-13 into the vascular compartment was detected in the early period after CPB. This release of MMP-13 occurred in patients undergoing routine elective coronary revascularization and with hemodynamic profiles within normal limits before starting CPB. In the present study, the emergence of another group of MMPs was observed to occur in the period after CPB. Specifically, plasma levels of the gelatinases MMP-2 and MMP-9 increased in the early postoperative period. This group of MMPs were originally classified based on the ability to degrade denatured collagen, or gelatin. However, MMP-2 and MMP-9 degrade a wide variety of interstitial proteins that include basement membrane components. The induction of MMP-2 and MMP-9 have been demonstrated in several cardiovascular disease states including atheromatous plaques, aneurysms, and after myocardial infarction [9–11, 15–18]. The unique results from the present study demonstrated that a specific portfolio of MMPs was released in a time-dependent fashion after CPB.

In light of the potent proteolytic activity of MMPs, enzymatic activity is tightly regulated at three levels: transcription, posttranslational modification, and inhibition. Transcriptional activity of MMP mRNA is under the influence of a number of promoter regions located upstream from the specific MMP DNA coding sequence [13, 15]. A number of physical and biochemical signals can induce the formation of transcription factors, which bind to these promoter regions and facilitate the synthesis of MMP transcripts. Several of the MMP genes contain elements in the promoter region that bind proto-oncogene products of the fos and jun family [13, 15, 20]. Bioactive peptides and cytokines, such as tumor necrosis factor-α, stimulate the production of these proto-oncogenes, and have been demonstrated to increase MMP transcription in several cell systems [13, 15, 20]. Increased cytokine activation such as augmented levels of tumor necrosis factor-α has been reported to occur during and after CPB [3, 21, 22]. However, the relationship between cytokine activation and MMP synthesis/release in the period after CPB remains to be established. In the present study, plasma levels for several MMP species acutely increased at separation from CPB. For example, MMP-8 increased by more than fivefold at separation from CPB. This time frame for the emergence of MMP-8 is unlikely to be the result of increased transcription, but rather the release of endogenous stores of this enzyme. On the other hand, increased plasma levels of MMP-2 occurred at much later postoperative time points. One potential contributory factor for the increase in MMP-2, which occurred in the late postoperative period, is enhanced MMP-2 transcription. On the basis of the results from the present study, future studies that more carefully focus on the transcriptional regulation of MMPs in the postcardiac surgical setting would be warranted. MMPs are synthesized and released into the extracellular space in a proenzyme or zymogen form. These pro-MMPs bind to different proteins within the interstitial space and remain quiescent until activated. The activation process of MMPs is an important regulatory step [23]. Activation requires a number of integrated and step-wise biochemical events to occur to yield a fully active MMP. Briefly, cleavage of the propeptide domain can occur through proteolytic processing by serine proteases such as plasmin or by a group of membrane type MMPs called the MT-MMPs [23]. This removal of the propeptide domain exposes the MMP catalytic moiety and yields an active enzyme. The present study quantified MMP plasma levels using antisera that recognized primarily the proenzyme and therefore, the actual amount of active MMP could not be directly determined. The decrease in pro-MMP-2 levels in the plasma as well as in the coronary sinus relative to proximal aorta immediately after CPB is suggestive of activation of the proenzyme. Although this issue remains speculative, the increased plasma levels of pro-MMP species that occurred after CPB reflect a significant augmentation of the recruitable enzyme pool, which in turn would result in a net gain in MMP activity. An important control point of MMP activity is the tissue inhibitors of matrix metalloproteinases (TIMPs) [8, 13, 15, 16, 18, 23]. The TIMPs are low molecular weight proteins that bind to activated MMPs in a 1:1 stoichiometric ratio. Past clinical studies have demonstrated that alterations in TIMP inhibitory control occur within the myocardium in chronic heart failure and diminished TIMP levels have been associated with plaque rupture [10, 14]. The present study measured the absolute abundance of MMP species appearing within the plasma during and after CPB. Whether and to what degree TIMP plasma levels parallel these changes in MMP species abundance after CPB remains to be established.

The present study demonstrated that a specific profile of MMPs is released into the vascular compartment during and after CPB. These plasma levels likely reflect spillover from several cellular compartments. With respect to MMP-8, the primary site of synthesis and storage is the neutrophil [19]. Extracorporeal circulation can induce neutrophil degranulation, which in turn would result in a release of MMP-8 into the circulation [3, 22]. The rapid increase and decrease of MMP-8 plasma levels that occurred immediately after separation from the CPB circuit is consistent with a release of endogenous stores of this MMP species. MMP-13 has been primarily localized to carcinoma cell lines, but recent studies have suggested that MMP-13 can by synthesized by a number of cell types [14, 19]. This laboratory recently identified MMP-13 within the human myocardium in both healthy subjects and patients with chronic heart failure [14]. These past findings coupled with the present study suggest that the synthesis and release of MMP-13 is not restricted to local expression within neoplasms. The synthesis and release of gelatinase MMP-9 has been demonstrated to occur in a number of cell and tissue types [15, 16, 24]. One important source of MMP-9 is neutrophils and macrophages. Thus, stimulation of neutrophils during the conduct of CPB may have facilitated the release of MMP-9. The majority of cell types within the myocardium including myocytes are capable of MMP-2 synthesis and release [5, 10, 14, 24]. The positive pro-MMP-2 myocardial gradient that occurred before CPB suggest that one contributory source for detectable levels of pro-MMP-2 within the plasma is the myocardium. Interestingly, at cross-clamp release, the myocardial pro-MMP-2 gradient became negative suggesting increased activation or sequestration of this MMP species within the myocardial circuit. This temporal change of pro-MMP-2 abundance within the myocardial circuit was paralleled by a reduction in absolute levels of pro-MMP-2 within the systemic circulation. However, it remains to be established whether the myocardium is a significant source for certain MMP species that are released into the vascular compartment after CPB.

The MMPs are important in many forms of tissue remodeling, both physiologic and pathologic. For example, embryogenesis, ovulation, wound/fracture healing, angiogensis, and normal neutrophil and macrophage function depend on the proteolytic action of MMPs [15–20]. Overexpression of MMP subtypes has been associated with the pathologic ultrastructural changes of left ventricular remodeling in congestive heart failure, aortic aneurysms, and atherosclerotic plaque development and rupture [7–10, 14, 18]. Acute elevations in MMP concentration has also been observed in the acute coronary syndromes of unstable angina and acute myocardial infarction [8, 9]. The present study quantitated certain MMP species within the plasma of patients undergoing elective coronary revascularization and requiring CPB. Although the temporal profile of certain MMP species within the systemic circulation during and after CPB was defined, a mechanistic relationship between MMP release and postoperative outcomes was not determined. Past studies have demonstrated alterations in microvascular protein permeability with a subsequent increase in extravascular tissue water content in several organ systems after CPB [1, 2, 21, 25]. The egress of proteins from the vascular space is likely due to increased microvascular pore size, reflecting endothelial damage or an alteration in the extracellular matrix. The present study demonstrated increased release of a portfolio of MMP subtypes specific for basement membrane components and interstitial collagens, which may directly facilitate changes in vascular permeability. Future studies that measure MMP levels in a much larger and diverse group of patients undergoing cardiac procedures will be necessary to establish a potential cause–effect relationship between MMP release and specific determinants of the postoperative course. These future studies would hold clinical relevance in light of the fact that specific interventional strategies could be developed that would interfere with MMP synthesis and expression. Specifically, inhibition of cytokine receptor activation, such as through the use of a soluble tumor necrosis factor-α binding protein in the period after CPB may reduce MMP synthesis and release [26]. In addition, pharmacologic inhibitors of MMP activity have been developed and successfully used in animal models of cardiovascular disease [18]. Thus, elucidation of the mechanisms and consequences of enhanced MMP release in the early CPB setting may yield novel therapeutic strategies.

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